3 - World Journal of Gastroenterology

World Journal of 

Radiology 

World J Radiol 2011 March 28; 3(3): 55-84 

www.wjgnet.com 

ISSN 1949-8470 (online)

W J R 

PRESIDENT AND EDITOR-IN- 

CHIEF 

Lian-Sheng Ma, Beijing 

STRATEGY ASSOCIATE 

EDITORS-IN-CHIEF 

Ritesh Agarwal, Chandigarh 

Kenneth Coenegrachts, Bruges 

Mannudeep K Kalra, Boston 

Meng Law, Lost Angeles 

Ewald Moser, Vienna 

Aytekin Oto, Chicago 

AAK Abdel Razek, Mansoura 

Àlex Rovira, Barcelona 

Yi-Xiang Wang, Hong Kong 

Hui-Xiong Xu, Guangzhou 

GUEST EDITORIAL BOARD 

MEMBERS 

Wing P Chan, Taipei 

Wen-Chen Huang, Taipei 

Shi-Long Lian, Kaohsiung 

Chao-Bao Luo, Taipei 

Shu-Hang Ng, Taoyuan 

Pao-Sheng Yen, Haulien 

MEMBERS OF THE EDITORIAL 

BOARD 

Australia 

Karol Miller, Perth 

Tomas Kron, Melbourne 

Zhonghua Sun, Perth 

Austria 

Herwig R Cerwenka, Graz 

Editorial Board 

2009-2013 

The World Journal of Radiology Editorial Board consists of 319 members, representing a team of worldwide experts 

in radiology. They are from 40 countries, including Australia (3), Austria (4), Belgium (5), Brazil (3), Canada (9), 

Chile (1), China (25), Czech (1), Denmark (1), Egypt (4), Estonia (1), Finland (1), France (6), Germany (17), Greece 

(8), Hungary (1), India (9), Iran (5), Ireland (1), Israel (4), Italy (28), Japan (14), Lebanon (1), Libya (1), Malaysia (2), 

Mexico (1), Netherlands (4), New Zealand (1), Norway (1), Saudi Arabia (3), Serbia (1), Singapore (2), Slovakia (1), 

South Korea (16), Spain (8), Switzerland (5), Thailand (1), Turkey (20), United Kingdom (16), and United States (82). 

WJR|www.wjgnet.com 


Radiology 

Daniela Prayer,Vienna 

Siegfried Trattnig, Vienna 

Belgium 

Piet R Dirix, Leuven 

Yicheng Ni, Leuven 

Piet Vanhoenacker, Aalst 

Jean-Louis Vincent, Brussels 

Brazil 

Emerson L Gasparetto, Rio de Janeiro 

Edson Marchiori, Petrópolis 

Wellington P Martins, São Paulo 

Canada 

Sriharsha Athreya, Hamilton 

Mark Otto Baerlocher, Toronto 

Martin Charron, Toronto 

James Chow, Toronto 

John Martin Kirby, Hamilton 

Piyush Kumar, Edmonton 

Catherine Limperpoulos, Quebec 

Ernest K Osei, Kitchener 

Weiguang Yao, Sudbury 

Chile 

Masami Yamamoto, Santiago 

China 

Feng Chen, Nanjing 

Ying-Sheng Cheng, Shanghai 

Woei-Chyn Chu, Taipei 

Guo-Guang Fan, Shenyang 

Shen Fu, Shanghai 

Gang Jin, Beijing 

Tak Yeung Leung, Hong Kong 

Wen-Bin Li, Shanghai 

Rico Liu, Hong Kong 

Yi-Yao Liu, Chengdu 

Wei Lu, Guangdong 

Fu-Hua Peng, Guangzhou 

Li-Jun Wu, Hefei 

Zhi-Gang Yang, Chengdu 

Xiao-Ming Zhang, Nanchong 

Chun-Jiu Zhong, Shanghai 

Czech 

Vlastimil Válek, Brno 

Denmark 

Poul Erik Andersen, Odense 

Egypt 

Mohamed Abou El-Ghar, Mansoura 

Mohamed Ragab Nouh, Alexandria 

Ahmed A Shokeir, Mansoura 

Estonia 

Tiina Talvik, Tartu 

Finland 

Tove J Grönroos, Turku 

I March 28, 2011

France 

Alain Chapel, Fontenay-Aux-Roses 

Nathalie Lassau, Villejuif 

Youlia M Kirova, Paris 

Géraldine Le Duc, Grenoble Cedex 

Laurent Pierot, Reims 

Frank Pilleul, Lyon 

Pascal Pommier, Lyon 

Germany 

Ambros J Beer, München 

Thomas Deserno, Aachen 

Frederik L Giesel, Heidelberg 

Ulf Jensen, Kiel 

Markus Sebastian Juchems, Ulm 

Kai U Juergens, Bremen 

Melanie Kettering, Jena 

Jennifer Linn, Munich 

Christian Lohrmann, Freiburg 

David Maintz, Münster 

Henrik J Michaely, Mannheim 

Oliver Micke, Bielefeld 

Thoralf Niendorf, Berlin-Buch 

Silvia Obenauer, Duesseldorf 

Steffen Rickes, Halberstadt 

Lars V Baron von Engelhardt, Bochum 

Goetz H Welsch, Erlangen 

Greece 

Panagiotis Antoniou, Alexandroupolis 

George C Kagadis, Rion 

Dimitris Karacostas, Thessaloniki 

George Panayiotakis, Patras 

Alexander D Rapidis, Athens 

C Triantopoulou, Athens 

Ioannis Tsalafoutas, Athens 

Virginia Tsapaki, Anixi 

Ioannis Valais, Athens 

Hungary 

Peter Laszlo Lakatos, Budapest 

India 

Anil Kumar Anand, New Delhi 

Surendra Babu, Tamilnadu 

Sandip Basu, Bombay 

Kundan Singh Chufal, New Delhi 

Shivanand Gamanagatti, New Delhi 

Vimoj J Nair, Haryana 

R Prabhakar, New Delhi 

Sanjeeb Kumar Sahoo, Orissa 

Iran 

Vahid Reza Dabbagh Kakhki, Mashhad 

Mehran Karimi, Shiraz 

Farideh Nejat, Tehran 

Alireza Shirazi, Tehran 

Hadi Rokni Yazdi, Tehran 


Ireland 

Joseph Simon Butler, Dublin 

Israel 

Amit Gefen, Tel Aviv 

Eyal Sheiner, Be’er-Sheva 

Jacob Sosna, Jerusalem 

Simcha Yagel, Jerusalem 

Italy 

Mohssen Ansarin, Milan 

Stefano Arcangeli, Rome 

Tommaso Bartalena, Imola 

Filippo Cademartiri, Parma 

Sergio Casciaro, Lecce 

Laura Crocetti, Pisa 

Alberto Cuocolo, Napoli 

Mirko D’Onofrio, Verona 

Massimo Filippi, Milan 

Claudio Fiorino, Milano 

Alessandro Franchello, Turin 

Roberto Grassi, Naples 

Stefano Guerriero, Cagliari 

Francesco Lassandro, Napoli 

Nicola Limbucci, L'Aquila 

Raffaele Lodi, Bologna 

Francesca Maccioni, Rome 

Laura Martincich, Candiolo 

Mario Mascalchi, Florence 

Roberto Miraglia, Palermo 

Eugenio Picano, Pisa 

Antonio Pinto, Naples 

Stefania Romano, Naples 

Luca Saba, Cagliari 

Sergio Sartori, Ferrara 

Mariano Scaglione, Castel Volturno 

Lidia Strigari, Rome 

Vincenzo Valentini, Rome 

Japan 

Shigeru Ehara, Morioka 

Nobuyuki Hamada, Chiba 

Takao Hiraki, Okayama 

Akio Hiwatashi, Fukuoka 

Masahiro Jinzaki, Tokyo 

Hiroshi Matsuda, Saitama 

Yasunori Minami, Osaka 

Jun-Ichi Nishizawa, Tokyo 

Tetsu Niwa, Yokohama 

Kazushi Numata, Kanagawa 

Kazuhiko Ogawa, Okinawa 

Hitoshi Shibuya, Tokyo 

Akira Uchino, Saitama 

Haiquan Yang, Kanagawa 

Lebanon 

Aghiad Al-Kutoubi, Beirut 

Libya 

Anuj Mishra, Tripoli 

Malaysia 

R Logeswaran, Cyberjaya 

Kwan-Hoong Ng, Kuala Lumpur 

Mexico 

Heriberto Medina-Franco, Mexico City 

Netherlands 

Jurgen J Fütterer, Nijmegen 

Raffaella Rossin, Eindhoven 

Paul E Sijens, Groningen 

Willem Jan van Rooij, Tilburg 

New Zealand 

W Howell Round, Hamilton 

Norway 

Arne Sigmund Borthne, Lørenskog 

Saudi Arabia 

Mohammed Al-Omran, Riyadh 

Ragab Hani Donkol, Abha 

Volker Rudat, Al Khobar 

Serbia 

Djordjije Saranovic, Belgrade 

Singapore 

Uei Pua, Singapore 

Lim CC Tchoyoson, Singapore 

Slovakia 

František Dubecký, Bratislava 

South Korea 

Bo-Young Choe, Seoul 

Joon Koo Han, Seoul 

Seung Jae Huh, Seoul 

Chan Kyo Kim, Seoul 

Myeong-Jin Kim, Seoul 

Seung Hyup Kim, Seoul 

Kyoung Ho Lee, Gyeonggi-do 

Won-Jin Moon, Seoul 

Wazir Muhammad, Daegu 

Jai Soung Park, Bucheon 

Noh Hyuck Park, Kyunggi 

Sang-Hyun Park, Daejeon 

Joon Beom Seo, Seoul 

Ji-Hoon Shin, Seoul 

Jin-Suck Suh, Seoul 

Hong-Gyun Wu, Seoul 

II March 28, 2011

Spain 

Eduardo J Aguilar, Valencia 

Miguel Alcaraz, Murcia 

Juan Luis Alcazar, Pamplona 

Gorka Bastarrika, Pamplona 

Rafael Martínez-Monge, Pamplona 

Alberto Muñoz, Madrid 

Joan C Vilanova, Girona 

Switzerland 

Nicolau Beckmann, Basel 

Silke Grabherr, Lausanne 

Karl-Olof Lövblad, Geneva 

Tilo Niemann, Basel 

Martin A Walter, Basel 

Thailand 

Sudsriluk Sampatchalit, Bangkok 

Turkey 

Olus Api, Istanbul 

Kubilay Aydin, İstanbul 

Işıl Bilgen, Izmir 

Zulkif Bozgeyik, Elazig 

Barbaros E Çil, Ankara 

Gulgun Engin, Istanbul 

M Fatih Evcimik, Malatya 

Ahmet Kaan Gündüz, Ankara 

Tayfun Hakan, Istanbul 

Adnan Kabaalioglu, Antalya 

Fehmi Kaçmaz, Ankara 

Musturay Karcaaltincaba, Ankara 

Osman Kizilkilic, Istanbul 

Zafer Koc, Adana 

Cem Onal, Adana 

Yahya Paksoy, Konya 

Bunyamin Sahin, Samsun 

Ercument Unlu, Edirne 

Ahmet Tuncay Turgut, Ankara 

Ender Uysal, Istanbul 


United Kingdom 

K Faulkner, Wallsend 

Peter Gaines, Sheffield 

Balaji Ganeshan, Brighton 

Nagy Habib, London 

Alan Jackson, Manchester 

Pradesh Kumar, Portsmouth 

Tarik F Massoud, Cambridge 

Igor Meglinski, Bedfordshire 

Robert Morgan, London 

Ian Negus, Bristol 

Georgios A Plataniotis, Aberdeen 

N J Raine-Fenning, Nottingham 

Manuchehr Soleimani, Bath 

MY Tseng, Nottingham 

Edwin JR van Beek, Edinburgh 

Feng Wu, Oxford 

United States 

Athanassios Argiris, Pittsburgh 

Stephen R Baker, Newark 

Lia Bartella, New York 

Charles Bellows, New Orleans 

Walter L Biffl, Denver 

Homer S Black, Houston 

Wessam Bou-Assaly, Ann Arbor 

Owen Carmichael, Davis 

Shelton D Caruthers, St Louis 

Yuhchyau Chen, Rochester 

Melvin E Clouse, Boston 

Ezra Eddy Wyssam Cohen, Chicago 

Aaron Cohen-Gadol, Indianapolis 

Patrick M Colletti, Los Angeles 

Kassa Darge, Philadelphia 

Abhijit P Datir, Miami 

Delia C DeBuc, Miami 

Russell L Deter, Houston 

Adam P Dicker, Phil 

Khaled M Elsayes, Ann Arbor 

Steven Feigenberg, Baltimore 

Christopher G Filippi, Burlington 

Victor Frenkel, Bethesda 

Thomas J George Jr, Gainesville 

Patrick K Ha, Baltimore 

Robert I Haddad, Boston 

Walter A Hall, Syracuse 

Mary S Hammes, Chicago 

John Hart Jr, Dallas 

Randall T Higashida, San Francisco 

Juebin Huang, Jackson 

Andrei Iagaru, Stanford 

Craig Johnson, Milwaukee 

Ella F Jones, San Francisco 

Csaba Juhasz, Detroit 

Riyad Karmy-Jones, Vancouver 

Daniel J Kelley, Madison 

Amir Khan, Longview 

Euishin Edmund Kim, Houston 

Vikas Kundra, Houston 

Kennith F Layton, Dallas 

Rui Liao, Princeton 

CM Charlie Ma, Philadelphia 

Nina A Mayr, Columbus 

Thomas J Meade, Evanston 

Steven R Messé, Philadelphia 

Nathan Olivier Mewton, Baltimore 

Feroze B Mohamed, Philadelphia 

Koenraad J Mortele, Boston 

Mohan Natarajan, San Antonio 

John L Nosher, New Brunswick 

Chong-Xian Pan, Sacramento 

Dipanjan Pan, St Louis 

Martin R Prince, New York 

Reza Rahbar, Boston 

Carlos S Restrepo, San Antonio 

Veronica Rooks, Honolulu 

Maythem Saeed, San Francisco 

Edgar A Samaniego, Palo Alto 

Kohkan Shamsi, Doylestown 

Jason P Sheehan, Charlottesville 

William P Sheehan, Willmar 

Charles Jeffrey Smith, Columbia 

Monvadi B Srichai-Parsia, New York 

Dan Stoianovici, Baltimore 

Janio Szklaruk, Houston 

Dian Wang, Milwaukee 

Jian Z Wang, Columbus 

Liang Wang, New York 

Shougang Wang, Santa Clara 

Wenbao Wang, New York 

Aaron H Wolfson, Miami 

Gayle E Woloschak, Chicago 

Ying Xiao, Philadelphia 

Juan Xu, Pittsburgh 

Benjamin M Yeh, San Francisco 

Terry T Yoshizumi, Durham 

Jinxing Yu, Richmond 

Jianhui Zhong, Rochester 

III March 28, 2011

W J R 

Contents 

EDITORIAL 

REVIEW 

ORIGINAL ARTICLES 

CASE REPORT 



Radiology 

55 A promising diagnostic method: Terahertz pulsed imaging and spectroscopy 

Sun Y, Sy MY, Wang YXJ, Ahuja AT, Zhang YT, Pickwell-MacPherson E 

66 Applications of new irradiation modalities in patients with lymphoma: 

Promises and uncertainties 

Kirova YM, Chargari C 

70 Estimation of intra-operator variability in perfusion parameter measurements 

using DCE-US 

Gauthier M, Leguerney I, Thalmensi J, Chebil M, Parisot S, Peronneau P, Roche A, 

Lassau N 

Monthly Volume 3 Number 3 March 28, 2011 

82 Paraparesis induced by extramedullary haematopoiesis 

Savini P, Lanzi A, Marano G, Moretti CC, Poletti G, Musardo G, Foschi FG, Stefanini GF 

March 28, 2011|Volume 3| ssue 3|

Contents 

ACKNOWLEDGMENTS 

APPENDIX 

ABOUT COVER 

AIM AND SCOPE 

FLYLEAF 

EDITORS FOR 

THIS ISSUE 

NAME OF JOURNAL 

World Journal of Radiology 

LAUNCH DATE 

December 31, 2009 

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Volume 3 Number 3 March 28, 2011 

I Acknowledgments to reviewers of World Journal of Radiology 

I Meetings 

I-V Instructions to authors 

Sun Y, Sy MY, Wang YXJ, Ahuja AT, Zhang YT, Pickwell-MacPherson E. A 

promising diagnostic method: Terahertz pulsed imaging and spectroscopy. 

World J Radiol 2011; 3(3): 55-65 

http://www.wjgnet.com/1949-8470/full/v3/i3/55.htm 

World Journal of Radiology (World J Radiol, WJR, online ISSN 1949-8470, DOI: 10.4329) is 

a monthly peer-reviewed, online, open-access, journal supported by an editorial board 

consisting of 319 experts in radiology from 40 countries. 

The major task of WJR is to rapidly report the most recent improvement in the 

research of medical imaging and radiation therapy by the radiologists. WJR accepts 

papers on the following aspects related to radiology: Abdominal radiology, women 

health radiology, cardiovascular radiology, chest radiology, genitourinary radiology, 

neuroradiology, head and neck radiology, interventional radiology, musculoskeletal 

radiology, molecular imaging, pediatric radiology, experimental radiology, radiological 

technology, nuclear medicine, PACS and radiology informatics, and ultrasound. We also 

encourage papers that cover all other areas of radiology as well as basic research. 

I-III Editorial Board 

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PUBLICATION DATE 

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SERIAL PUBLICATION NUMBER 

ISSN 1949-8470 (online) 

PRESIDENT AND EDITOR-IN-CHIEF 

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STRATEGY ASSOCIATE EDITORS-IN-CHIEF 

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Meng Law, Lost Angeles 

Ewald Moser, Vienna 

Aytekin Oto, Chicago 

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Hui-Xiong Xu, Guangzhou 

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wjr@wjgnet.com 

doi:10.4329/wjr.v3.i3.55 

A promising diagnostic method: Terahertz pulsed imaging 

and spectroscopy 

Yiwen Sun, Ming Yiu Sy, Yi-Xiang J Wang, Anil T Ahuja, Yuan-Ting Zhang, Emma Pickwell-MacPherson 

Yiwen Sun, Ming Yiu Sy, Yuan-ting Zhang, Department of 

Electronic Engineering, The Chinese University of Hong Kong, 

Hong Kong, China 

Yi-Xiang J Wang, Anil T Ahuja, Department of Imaging and 

Interventional Radiology, The Chinese University of Hong Kong, 


Yuan-ting Zhang, The Institute of Biomedical and Health Engineering, 

Shenzhen Instituted of Advanced Technology, Chinese 

Academy of Sciences, Shenzhen 518000, Guangdong Province, 

China 

Yuan-Tng Zhang, Key Laboratory for Biomedical Informatics 

and Health Engineering, Chinese Academy of Sciences, Shenzhen 

518000, Guangdong Province, China 

Emma Pickwell-MacPherson, Department of Electronic and 

Computer Engineering, Hong Kong University of Science and 

Technology, Hong Kong, China 

Author contributions: Wang YXJ gave the idea of the paper was 

given; Sun Y, Sy MY and Pickwell-MacPherson E collected the 

data presented; all authors were involved in writing and editing 

the paper. 

Supported by in part for this work from the Research Grants 

Council of the Hong Kong Government and the Shun Hing Institute 

of Advanced Engineering, Hong Kong 

Correspondence to: Dr. Emma Pickwell-MacPherson, Department 

of Electronic and Computer Engineering, Hong Kong 

University of Science and Technology, Hong Kong, 

China. eeemma@ust.hk 

Telephone: +852-23585034 Fax: +852-23581485 

Received: November 18, 2010 Revised: January 19, 2010 

Accepted: January 26, 2010 

Published online: March 28, 2011 

Abstract 

The terahertz band lies between the microwave and infrared 

regions of the electromagnetic spectrum. This radiation 

has very low photon energy and thus it does not 

pose any ionization hazard for biological tissues. It is 

strongly attenuated by water and very sensitive to water 

content. Unique absorption spectra due to intermolecular 

vibrations in this region have been found in different 

biological materials. These unique features make tera- 



Radiology 

hertz imaging very attractive for medical applications in 

order to provide complimentary information to existing 

imaging techniques. There has been an increasing interest 

in terahertz imaging and spectroscopy of biologically 

related applications within the last few years and more 

and more terahertz spectra are being reported. This 

paper introduces terahertz technology and provides a 

short review of recent advances in terahertz imaging 

and spectroscopy techniques, and a number of applications 

such as molecular spectroscopy, tissue characterization 

and skin imaging are discussed. 

© 2011 Baishideng. All rights reserved. 

Key words: Biomedical; Imaging; Spectroscopy; Terahertz 

Peer reviewer: Yicheng Ni, MD, PhD, Professor, Biomedical 

Imaging, Interventional Therapy and Contrast Media Research, 

Department of Radiology, University Hospitals, K.U. Leuven, 

Herestraat 49, B-3000, Leuven, Belgium 

Sun Y, Sy MY, Wang YXJ, Ahuja AT, Zhang YT, Pickwell- 

MacPherson E. A promising diagnostic method: Terahertz pulsed 

imaging and spectroscopy. World J Radiol 2011; 3(3): 55-65 

Available from: URL: http://www.wjgnet.com/1949-8470/full/ 

v3/i3/55.htm DOI: http://dx.doi.org/10.4329/wjr.v3.i3.55 

INTRODUCTION 




EDITORIAL 

Terahertz (THz, 1 THz = 10 12 Hz) radiation, also known 

as THz waves, THz light, or T-rays, is situated in the frequency 

regime between optical and electronic techniques. 

This regime is typically defined as 0.1-10 THz and has 

become a new area for research in physics, chemistry, biology, 

materials science and medicine. Experiments with 

THz radiation date back to measurements of black body 

radiation using a bolometer in the 1890s [1,2] . However, 

for a long time, this region remained unexplored due to a 

lack of good sources and detectors, and it was commonly 

55 March 28, 2011|Volume 3|Issue 3|

Sun Y et al . Terahertz pulsed imaging and spectroscopy 

referred to as the “THz gap”. In 1975, David Auston at 

AT&T Bell Laboratories developed a photoconductive 

emitter gated with an optical pulse that led towards bridging 

this gap - the ‘Auston switch’ emitted broadband THz 

radiation up to 1 mW. A coherent method to detect THz 

pulses in the time domain was also proposed [3] . This became 

the foundation of THz time-domain spectroscopy 

(THz-TDS) [4] , since then many improvements in the generation 

and detection of coherent THz radiation enabled 

THz-TDS and imaging techniques to be pioneered for 

applications in various fields such as biomedical engineering, 

physics, astronomy, security screening, communications, 

genetic engineering, pharmaceutical quality control 

and medical imaging [5] . In this paper, THz technology is 

introduced and some emerging applications in biology 

and medicine including molecular spectroscopy, tissue 

characterization and skin imaging are presented. 

The aim of this article is to review the potential of 

THz pulsed imaging and spectroscopy as a promising 

diagnostic method. Several unique features make THz 

very suitable for medical applications. (1) THz radiation 

has very low photon energy, which is insufficient to cause 

chemical damage to molecules, or knock particles out 

of atoms. Thus, it will not cause harmful ionization in 

biological tissues; this makes it very attractive for medical 

applications; (2) THz radiation is very sensitive to polar 

substances, such as water and hydration state. For this 

reason, THz waves can provide a better contrast for soft 

tissues than X-rays; (3) THz-TDS techniques use coherent 

detection to record the THz wave’s temporal electric 

fields, which means both the amplitude and phase of the 

THz wave can be obtained simultaneously. The temporal 

waveforms can be further Fourier transformed to give the 

spectra. This allows precise measurements of the refractive 

index and absorption coefficient of samples without 

resorting to the Kramers-Kronig relations; and (4) The 

energy of rotational and vibrational transitions of molecules 

lies in the THz region and intermolecular vibrations 

such as hydrogen bonds exhibit different spectral characteristics 

in the THz range. These unique spectral features 

can be used to distinguish between different materials or 

even isomers. 

PRINCIPLES OF THZ PULSED IMAGING 

AND SPECTROSCOPY 

THz systems 

Over the past two decades, technology for generating and 

detecting THz radiation has advanced considerably. Several 

commercialized systems are now available [6-10] and THz 

systems have been set up by many groups all over the 

world. According to the laser source used, THz systems 

can be divided into two general classes: continuous wave 

(CW) and pulsed. 

A typical CW system can produce a single fixed frequency 

or several discrete frequency outputs. Some of 

them can be tunable. Generation of CW THz radiation 

can be achieved by approaches such as photomixing [11] , 


Laser diode1 

Laser diode2 

BS 

Emitter 

cw THz 

Sample 

Detector 

Delay 

Figure 1 Schematic illustration of a continuous wave THz imaging system 

in transmission geometry. 

Vitesse 

femtosecond 

pulsed laser 

Delay stage 

Probe 

beam 

Sample 

Quartz imaging plate 

Photoconductive 

emitter 

free-electron lasers [12] and quantum cascade lasers [13] . 

Figure 1 illustrates a CW THz system which photomixes 

two CW lasers in a photoconductor as an example [14] . The 

mixing of two above-bandgap (visible or near-infrared) 

wavelengths produces beating, which can modulate the 

conductance of a photoconductive switch at the THz 

difference frequency. The photomixing device is labeled 

“emitter” in Figure 1. Since the source spectrum of the 

CW system is narrow and sometimes only the intensity 

information is of interest, the data structures and postprocessing 

are relatively simple. It is possible now to 

drive a whole CW system by laser diodes and thus it can 

be made compact and inexpensive. However, due to the 

limited information that CW systems provide, they are 

sometimes confined to those applications where only features 

at some specific frequencies are of interest. 

In pulsed systems, broadband emission up to several 

THz can be achieved. Currently, there are a number of 

ways to generate and detect pulsed THz radiation, such 

as ultrafast switching of photoconductive antennas [3] , rectification 

of optical pulses in crystals [15] , rapid screening 

of the surface field via photoexcitation of dense electron 

hole plasma in semiconductors [16] and carrier tunneling in 

coupled double quantum well structures [17] . Among them, 

the most established approaches based on photoconductive 

antennas, where an expensive femtosecond laser is 

required and configured as shown in Figure 2. Unlike CW 

THz imaging system, coherent detection in pulsed THz 

imaging techniques can record THz waves in the time do- 

56 March 28, 2011|Volume 3|Issue 3| 

30° 

Photoconductive 

detector 

Pump beam 

Figure 2 Schematic illustration of a pulsed THz imaging system with reflection 

geometry.

Rotations 

Vibrations 

Water 

H-bonds 

main, including both the intensity and phase information, 

which can be further used to obtain more details of the 

target such as spectral and depth information [18] . This key 

advantage lends coherent THz imaging to a wider range 

of applications. 

Molecular interactions in the THz regime 

There has been an increased interest in understanding the 

interactions between molecules and THz radiation. Many 

of the intricate interactions on a molecular level rely on 

changes in biomolecular conformation of the basic units 

of proteins such as α helices and β sheets. In recent years, 

dynamic signatures of the THz frequency vibrations in 

RNA and DNA strands have been characterized [19,20] . 

Furthermore, studies of water molecule interactions with 

proteins have attracted significant research interest [21] . In 

a protein-water network, the protein’s structure and dynamics 

are affected by the surrounding water which is 

called biological water, or hydration water. As illustrated 

in Figure 3, hydrogen bonds, which are weak attractive 

forces, form between the hydrated water molecules and 

the side chains of protein. These affect the dynamic relaxation 

properties of protein and enable distinction between 

the hydration water layer and bulk water. The remarkable 

effects of the hydrogen bonds associated with the intermolecular 

information are able to be detected using THz 

spectroscopy. THz spectra contain information about intermolecular 

modes as well as intra-molecular bonds and 

thus usually carry more structural information than vibrations 

in the mid-infrared spectral region which tend to be 

dominated by intra-molecular vibrations. 

Unique advantages and challenges for biomedical 

applications 

The energy level of 1 THz is only about 4.14 meV (which 

is much less than the energy of X-rays 0.12 to 120 keV), 

it therefore does not pose an ionization hazard as in X-ray 


Biomolecule 

H-bonds 

Figure 3 Schematic representation of H-bond interactions between water 

and biomolecules. 


radiation. Research into safe levels of exposure has also 

been carried out through studies on keratinocytes [22] and 

blood leukocytes [23,24] , neither of which has revealed any 

detectable alterations. This non-ionizing nature is a crucial 

property that lends THz techniques to medical applications. 

The fundamental period of THz-frequency electromagnetic 

radiation is around 1ps, and so it is uniquely 

suited to investigate biological systems with mechanisms 

at picosecond timescales. The energy levels of THz light 

are very low, therefore damage to cells or tissue should 

be limited to generalized thermal effects, i.e. strong resonant 

absorption seems unlikely. From a spectroscopy 

standpoint, biologically important collective modes of 

proteins vibrate at THz frequencies, in addition, frustrated 

rotations and collective modes cause polar liquids (such 

as water) to absorb at THz frequencies. Many organic 

substances have characteristic absorption spectra in this 

frequency range [25,26] enabling research into THz spectroscopy 

for biomedical applications. 

THz wavelengths have a diffraction limited spot size 

consistent with the resolution of a 1990’s vintage laser 

printer (1.22λ0 = 170 μm at 2.160 THz or 150 dots/in). 

At 1 THz, the resolution could be as good as a decent 

computer monitor (70 dots/in). Submillimeter-wavelength 

means that THz signals pass through tissue with only Mie 

or Tyndall scattering (proportional to f 2 ) rather than much 

stronger Rayleigh scattering (proportional to f 4 ) that dominates 

in the IR and optical since cell size is less than the 

wavelength. 

Since most tissues are immersed in, dominated by, or 

preserved in polar liquids, the exceptionally high absorption 

losses at THz frequencies make penetration through 

biological materials of any substantial thickness infeasible. 

However, the same high absorption coefficient that limits 

penetration in tissue also promotes extreme contrast between 

substances with lesser or higher degrees of water 

content which can help to show distinctive contrast in 

medical imaging. 

IMAGING VS SPECTROSCOPY 

THz pulsed imaging 

Early applications of THz technology were confined 

mostly to space science [27] and molecular spectroscopy [28,29] , 

but interest in biomedical applications has been increasing 

since the first introduction of THz pulsed imaging (TPI) 

in 1995 by Hu and Nuss [30] . Their THz images of porcine 

tissue demonstrated a contrast between muscle and fats. 

This initial study promoted later research on the application 

of THz imaging to other biological samples. THz pulsed 

imaging actually can be viewed as an extension of the THz- 

TDS method. In addition to providing valuable spectral 

information, 2D images can be obtained with THz-TDS by 

spatial scanning of either the THz beam or the object itself. 

In this way, geometrical images of the sample can be produced 

to reveal its inner structures [31] . Thus, it is possible to 

obtain three-dimensional views of a layered structure. 


A 

B 


Intensity (a.u., × 10 4 ) 

Spectral amplitude (a.u.) 

2.5 

2.0 

1.5 

1.0 

0.5 

0.0 

-0.5 

-1.0 

10 6 

10 5 

10 4 

10 3 

10 2 

10 1 

0.0 

-0.2 

-0.4 

15 25 

5 10 15 20 25 30 

Optical delay (ps) 

0 1 2 3 4 5 

Frequency (THz) 

Figure 4 Typical terahertz pulse and corresponding spectrum. A: Temporal 

waveform of a sample (drawn by raw data with the inset representing its corresponding 

processed data after deconvolution with a reference measurement); 

B: The corresponding spectrum of the raw data with the noise floor (indicated 

by dashed line). 

When a THz pulse is incident on such a target, a train 

of pulses will be reflected back from the various interfaces. 

For each individual pulse in the detected signal, the 

amplitude and timing are different and can be measured 

precisely. The principle of time of flight technique is to 

estimate the depth information of the internal dielectric 

profiles of the target through the time that is required to 

travel over a certain distance. This permits looking into 

the inside of optically opaque material and it has been 

used for THz 3D imaging. Among the earliest demonstrations 

of THz 3D imaging, Mittleman et al [31] imaged 

a conventional floppy disk. In their work the various 

parts inside the disk were identified and the discontinuous 

refractive index profile was derived. This method was 

further extended into THz reflection computed tomography 

[32,33] , where the target was rotated to provide back 

reflection from different angles. In a similar way to X-ray 

CT imaging, the filtered back projection algorithm was 

applied to reconstruct the edge map of the target’s crosssection. 

With advances in interactive publishing, Wallace 

et al [34] highlighted the ability of 3-D THz imaging in a 

number of niche applications. For example they were 

able to resolve two layers of drugs beneath the protective 

coating of a pharmaceutical tablet. 

THz spectroscopy 

THz spectroscopy is typically done with a single point 


measurement (with transmission geometry in most cases) 

of a homogenous sample and the resulting THz electric 

field can be recorded as a function of time. Thus, it can 

be Fourier transformed to offer meaningful spectroscopic 

information due to the broadband nature of pulsed THz 

radiation, shown in Figure 4. Although the spectral resolution 

is not as good as that with narrowband techniques, 

coherent detection of THz-TDS can provide both high 

sensitivity and time-resolved phase information [35] . This 

spectroscopic technique is primarily used to probe material 

properties and it is helpful to see where it lies in the 

electromagnetic spectrum in relation to atomic and molecular 

transitions. 

THz spectroscopy is complementary to THz imaging 

and is primarily used to determine optical properties in 

the frequency domain. Since THz pulses are created and 

detected using short pulsed visible lasers with pulse widths 

varying from approximately 200 fs down to approximately 

10 fs, it is now possible to make time resolved far-infrared 

studies with sub-picosecond temporal resolution [36] . This 

was not achievable with conventional far-infrared studies. 

An important aspect of THz time-domain spectroscopy 

is that both the phase and amplitude of the spectral components 

of the pulse are determined. The amplitude and 

phase are directly related to the absorption coefficient and 

refractive index of a sample and thus the complex permittivity 

is obtained without requiring Kramers-Kronig analysis. 

Furthermore, another advantage of THz spectroscopy 

is that it is able to non-destructively detect differences 

because it uses radiation of sufficiently long wavelength 

and low energy that does not induce any phase changes or 

photochemical reactions to living organisms. 

BIOLOGICAL APPLICATIONS 

Pharmaceuticals 

There has been a strong drive in the pharmaceutical industry 

for comprehensive quality assurance monitoring. 

This motivates development of new tools providing useful 

analysis of tablet formulations. The ability of THz 

technology to determine both spectral and structural 

information has fuelled interest in the pharmaceutical 

applications of this technique [37] . For example THz spectroscopy 

has been employed for polymorph identification 

and quantification [38] , phase transition monitoring [39] , and 

distinguishing between behaviors of hydrated forms [40] . 

THz radiation can penetrate through plastic packaging 

materials. To illustrate this we give an example using 

Maalox PlusTM - an over the counter medicine for stomach 

upsets. Each tablet has “Rorer” engraved on one side 

and “Maalox Plus” on the other side. Figure 5A contains 

a photo of a tablet in its packaging as well as a THz image 

taken after removing it from the packaging - the engraved 

lettering is clearly seen in the THz image. Figure 5C is a 

THz image of the tablet taken through the packaging - we 

can still see the lettering on the surface of the tablet. The 

cross-section of the tablet is better conveyed by an image 

of the depth profile. THz pulses are reflected first off the 


A 

C D 

Figure 5 Terahertz imaging of the tablet. A: Photograph of the tablet in the plastic package and THz C-Scan section imaging without the packaging; B: THz B-Scan 

image shows the structure of the cross-section of the tablet and the THz light paths at the edge of the tablet (path a) and the centre (path b); C: THz C-Scan image 

shows the tablet face inside the plastic package; D: THz deconvolved waveforms in the time-domain reflected from the paths a and b in Figure 5B. 

front surface of the package and then from any subsurface 

structure within it resulting in multiple pulses returning to 

the detector. The dashed arrows in Figure 5B mark out 

the THz light paths at the edge of the tablet (path A) and 

the center (path B). In path A the beveled edge means that 

there is an air gap between the packaging and the tablet 

and this corresponds to a greater optical delay between the 

reflected peaks in the waveforms illustrated in Figure 5D. 

Thus, THz imaging has non-destructively revealed the 

structure of the tablet through the packaging. 

Protein spectroscopy 

Towards the higher frequency end of the THz range (from 

about 1 THz and above) there are vibrational modes corresponding 

to protein tertiary structural motion; such 

intermolecular interactions are present in many biomolecules. 

Other molecular properties that can be probed in 

the THz range include bulk dielectric relaxation modes [41] 

and phonon modes [42] these can be difficult to probe using 

other techniques. For instance nuclear magnetic resonance 

(NMR) spectroscopy can determine the presence 

of various carbon bonds, but it cannot be used to distinguish 

between molecules with the same molecular formula, 

but with different structural forms (isomers) [10] . THz 

spectroscopy is able to distinguish between isomers and 

polymorphs [43] and is therefore emerging as an important 

and highly sensitive tool to determine biomolecular structure 

and dynamics [44,45] . Indeed THz spectroscopy can 


Amplitude (a.u.) 

B 

0.07 

0.06 

0.05 

0.04 

0.03 

0.02 

0.01 

0.00 

-0.01 

-0.02 

-0.03 


Surface of tablet Gap between tablet 

and package 

a b 

Dt = 2.14 ps 

Dt = 4.86 ps 

Surface of plastic 

package 

Path a 

Path b 

8 10 12 14 16 18 20 22 24 26 28 

Time (ps) 

distinguish between two types of artificial RNA strands 

when measured in dehydrated form [46] . Furthermore, 

Fischer et al [47] demonstrated that even when the molecular 

structure differs only in the orientation of a single hydroxyl 

group with respect to the ring plane, a pronounced 

difference in the THz spectra is observed. Intermolecular 

interactions are present in all biomolecules, and since biomolecules 

are the fundamental components of biological 

samples, they can be used to provide a natural source of 

image contrast in biomedical THz imaging [48] . 

Biomolecules, especially proteins, which play an essential 

structural and catalytic role in cells and tissues, often 

require an aqueous phase in order to be transported to their 

target sites. In the protein-water system, the characteristic 

water structure induced near the surfaces of proteins arises 

not only through hydrogen bonding of the water molecules 

to available proton donor and proton acceptor sites, but 

also through electrostatic forces associated with the water 

molecule that arise from its large electric dipole moment. 

If an electric field is applied to such a system of proteinassociated 

water, there will be a torque exerted on each water 

dipole moment inducing them to attempt to align along 

the direction of the field vector. The dielectric spectrum 

has been widely used to describe the interaction between 

protein and its solvent molecule in THz frequency [49] . A 

dielectric orientational relaxation time τ can then be defined 

as the time required for 1/e of the field-oriented water 

molecules to become randomly reoriented on removing 


A 

ε' 

B 

ε'' 


7.0 

6.5 

6.0 

5.5 

5.0 

4.5 

4.0 

3.5 

0.2 0.4 0.6 0.8 1.0 1.2 


3.0 

2.5 

2.0 

1.5 

0.76 THz 

the applied field. Measurements may be analyzed in terms 

of the complex dielectric constant ε(ω) (where ω denotes 

angular frequency) or the complex refractive index n(ω). 

The degree of orientational polarization and the rate of 

reorientational relaxation depend on how the water dipoles 

are influenced by local electrostatic forces and the extent 

to which the breaking and/or reforming of local hydrogen 

bonds is required to accommodate the changes in orientation. 

Relaxations of polar side-groups, vibrations of the 

polypeptide backbone, and fluctuating proton transfer 

between ionized side-groups of the protein also contribute 

to the overall polarizability of the protein-water system. 

If dielectric measurements are made on protein solutions, 

then orientational relaxations of the protein molecule itself 

will also be observed [50] . Figure 6 shows that the vibration 

mode of two types of labeled antibodies (peroxidase conjugated 

IgG and the fluorescein conjugated IgG) can be 

distinguished at 0.76 and 1.18 THz using the THz dielectric 

spectrum. By investigating the concentration dependence 

of the spectra it is also possible to obtain an estimate of the 

hydration shell thickness around the protein molecules [51] . 

MEDICAL APPLICATIONS 

Tissue characterization 

There is also interest in tissue contrast for in vivo and ex vivo 


Gly/water (1:1) 

PX-IgG (0.8 mg/mL) 

FITC-IgG (0.8 mg/mL) 

PX-IgG (0.8 mg/mL) 

Gly/water (1:1) 

FITC-IgG (0.8 mg/mL) 

1.18 THz 

1.0 

0.2 0.4 0.6 0.8 1.0 1.2 


Figure 6 Dielectric constant spectra (A) and dielectric loss spectra (B) of 

water/ glycerol mix (black line with circles), peroxidase conjugated IgG 

(red line with triangles) and the fluorescein conjugated IgG (green line 

with crosses) dissolved in the water/glycerol solution at the concentration 

of 0.8 mg/mL in the frequency range of 0.1-1.3 THz. PX: Peroxidase conjugated; 

FITC: Fluorescein conjugated. 

identification of abnormalities, hydration, and subdermal 

probing. Only a small number of measurements 

have been made to date, and systematic investigations to 

catalogue absorption coefficients, refractive indices and 

contrast mechanisms are just beginning to accumulate. 

Measurements on the absorption and refractive index of 

biological materials in the THz region go back at least to 

1976 [52] . Several research groups have investigated excised 

and fixed tissue samples, either alcohol perfused [8] , formalin 

fixed [53-57] , or freeze dried and wax mounted [58] looking 

for inherent contrast to define unique modalities. One of 

the first applications on human ex vivo wet tissue involved 

imaging of excised basal cell carcinoma [59,60] . In vivo work 

has focused on the skin [61] and accessible external surfaces 

of the body for measuring hydration [62] and tumor infiltration 

[60] . A catalogue of unfixed tissue properties (including 

blood constituents) was compiled by the University of 

Leeds, UK [54] for frequencies between 500-1500 GHz using 

a pulsed time-domain system. Difficulties in extrapolating 

measurements on excised tissue to in vivo results 

are numerous and include for example uptake of saline 

from the sample storage environment, changes in hydration 

level during measurement, temperature-dependent 

loss, measurement chamber interactions, and scattering 

effects. In our previous work [63] , we performed reflection 

geometry spectroscopy to investigate the properties 

of several types of healthy organ tissues, including liver, 

kidney, heart muscle, leg muscle, pancreas and abdominal 

fat tissues using THz pulsed imaging. The frequency dependent 

refractive index and the absorption coefficient of 

the tissues are shown in Figure 7. All the results are the 

mean values of the ten samples and error bars represent 

the 95% confidence intervals. We found clear differences 

between the tissue properties, particularly the absorption 

coefficient. Since fatty tissue largely consists of hydrocarbon 

chains and relatively few polar molecules, the absorption 

coefficient and refractive index of the fatty tissue are 

much lower that those of the kidney and liver tissues. 

We have also investigated the optical properties of 

fresh and formalin fixed samples in the THz frequency 

range using THz reflection spectroscopy [64] . As seen in 

Figure 8A, when the fixing time increased the waveform 

amplitude of the adipose tissue also increased. This was 

primarily because the refractive index of the adipose tissue 

was decreasing over the majority of the bandwidth 

(due to the fixing) and this meant there was a greater 

difference between the refractive index of the quartz (n 

approximately 2.1) and that of the adipose tissue (e.g. 1.5 

at 1 THz when fixed compared to 1.6 when it was fresh). 

From Fresnel theory, this increased difference in refractive 

indices resulted in a greater reflected amplitude. As the 

fixing time increased for the muscle, three main changes 

were apparent. A small peak started to appear preceding 

the trough and the width and magnitude of the trough 

decreased (Figure 8B). These changes can also be explained 

by considering the effects of the formalin on the 

refractive index and absorption coefficient of the muscle. 

For the muscle, the formalin significantly reduced both 


A 

Absorption coefficient (cm -1 ) 

250 

200 

150 

100 

50 

0 

0.25 0.50 0.75 1.00 1.25 1.50 


the refractive index and the absorption coefficient. Before 

fixing, the refractive index of the fresh muscle was greater 

than that of quartz over the whole of the frequency range 

measured (Figure 8C). The fixing reduced the refractive 

index so much that the refractive index became lower than 

that of quartz at higher frequencies (Figure 8D) and this 

was the cause for the small peak which appeared (arrow in 

Figure 8B) and increased as the fixing time was increased. 

Skin cancer, breast tumors and dental caries 

Due to the low penetration depth of THz in biological 

tissues, THz biomedical applications investigated to date 


Fat 

Liver 

Kidney 

B 

Refractive index 

2.8 

2.6 

2.4 

2.2 

2.0 

1.8 

1.6 

0.25 0.50 0.75 1.00 1.25 1.50 


Fat 

Liver 

Kidney 

Figure 7 Tissue characterization using THz spectroscopy. A: Mean absorption coefficients of kidney, liver and abdominal fat; B: Mean refractive indices of all the 

tissue samples. Error bars represent 95% confidence intervals. 

A 

C 



0.08 

0.07 

0.06 

0.05 

0.04 

0.03 

0.02 

0.01 

0.00 

Fresh fat 

Fixed fat (24 h) 



-0.01 

16.0 16.5 17.0 17.5 18.0 


3.3 

3.0 

2.7 

2.4 

2.1 

1.8 

1.5 

1.2 

Bulk water 

Fresh muscle 

Fresh fat 

0.1 0.3 0.5 0.7 0.9 1.1 


B 

D 



0.03 

0.02 

0.01 

0.00 

-0.01 

-0.02 

-0.03 

-0.04 

-0.05 

Fresh muscle 

Fixed muscle (24 h) 



-0.06 

15.5 16.0 16.5 17.0 17.5 18.0 18.5 19.0 19.5 


3.3 

3.0 

2.7 

2.4 

2.1 

1.8 

1.5 


Fixed muscle 

Fixed fat 

Quartz 

0.1 0.3 0.5 0.7 0.9 1.1 


Figure 8 The deconvolved mean waveforms for adipose tissue (A) and skeletal muscle (B) as the fixing time progressed and the mean refractive index for 

fresh (C) and fixed samples (D) of adipose tissue and skeletal muscle. The dot-dash line indicates the refractive index of the quartz window on which the sample 

was measured. Error bars represent 95% CI. The water data were acquired in transmission and the error bars are too small to be seen on this graph. 

have been limited to easily accessible parts of the body, 

such as skin and teeth, or those that would benefit from 

intra-operative imaging such as breast cancer. Figure 9 is a 

photograph of the reflection geometry THz probe from 

TeraView Ltd. which we use in Hong Kong. 

One potential application of THz imaging is the diagnosis 

of skin cancer. Work by Woodward et al [60] has demonstrated 

the potential to use THz imaging to determine 

regions of skin cancer non-invasively using a reflection 

geometry imaging system. The first ex vivo measurements 

on skin cancer revealing the ability of TPI to differentiate 

basal cell carcinoma (BCC) from normal skin were pro- 



Figure 9 Photograph of the THz hand-held probe. 

Incident 

THz pulse 

Gum 

Enamel 

Dentin 

Pulp 

duced by Woodward et al [59] . 

Breast-conserving surgery is also an area of medicine 

which may benefit from THz imaging. Fitzgerald et al [65] 

conducted ex vivo studies of breast cancer to investigate the 

potential of THz imaging to aid the removal of breast cancer 

intra-operatively. In particular, they studied the feasibility 

of THz pulsed imaging to map the tumor margins on 

freshly excised human breast tissue. Good correlation was 

found for the area and shape of tumor in the THz images 

compared with that of histology. They also performed a 

spectroscopy study comparing the THz optical properties 

(absorption coefficient and refractive index) of the excised 

normal breast tissue and breast tumor. Both the absorption 

coefficient and refractive index were higher for tissue that 

contained tumor and this is a very positive indication that 

THz imaging could be used to detect margins of tumor 

and provide complementary information to techniques 

such as infrared and optical imaging, thermography, electrical 

impedance, and magnetic resonance imaging [66,67] . 

Since in vivo THz imaging is currently limited to sur- 


1 

Detected pulse 

Figure 10 Schematic representation of the THz reflections from enamel. 

Reflection 1 is the reflection from the surface of the enamel and reflection 2 is 

the reflection from within the enamel due to tooth decay causing mineral loss. 

2 

1 

2 

Intensity (v) 

0.025 

0.015 

0.005 

-0.005 

-0.015 

-0.025 

-0.035 

14 16 18 20 22 24 


From palm and plaster 

From palm only 

Figure 11 Measured pulses from the palm. The blue line is the measurement 

of the palm through a tegaderm plaster and the red dotted line is the measurement 

of the palm alone. In both cases, two troughs are seen - they are the 

reflections from the top and bottom surfaces of the stratum corneum. 

face features, another potential application of THz imaging 

is the diagnosis of dental caries [68,69] . Figure 10 is a 

schematic diagram of a THz reflection from the outer 

layer of enamel. Caries are a result of mineral loss from 

enamel, and this causes a change in refractive index within 

the enamel. The change in refractive index means that 

small lesions, smaller than those detected by the naked 

eye, can be detected [70] . However, in practice THz imaging 

systems are large and cumbersome - even structures 

as obvious as teeth can make a challenging target. In this 

respect THz imaging is still some way off offering a nonionizing 

alternative to X-rays in dentistry. 

Burn depth diagnosis 

Since THz waves can penetrate several hundreds of microns 

into the skin and most burn injuries are superficial, 

this opens up the possibility of employing THz techniques 

for burn assessment [71] . The waveforms and optical 

parameters of the burn wounds were investigated and 

THz images have shown contrast between burn-damaged 

tissue and healthy tissue. Their results indicate that THz 

imaging may be promising in evaluating skin burn severity, 

especially for characterizing burn areas. Moreover, the 

time of flight technique is able to reveal the depth profile 

thus could be used to evaluate burn depth. 

The potential of THz imaging as a burn diagnostic 

has been demonstrated using chicken breast [6] . It is also 

conceivable that THz imaging could be of use in monitoring 

treatment of skin conditions (like psoriasis), since 

THz imaging is cheaper than MRI and does not require a 

coupling gel like ultrasound [72] . 

THz light can penetrate many materials: we have investigated 

whether it can resolve skin layers beneath a 

Tegaderm ® plaster as this would also be of benefit in 

monitoring burn wounds. Normal skin comprises three 

different layers: the stratum corneum, epidermis, and 

dermis. The stratum corneum on the palm of the hand 

is 100-200 μm thick and thus has been resolved in previous 

in vivo skin studies. We placed the plaster on the palm 

of the hand and the resulting THz reflected waveform 


A 

B 


14 

12 

10 

8 

6 

4 

2 

0 

2 4 6 8 10 12 

Position number 

Figure 12 In vivo measurement of the variation in stratum corneum 

thickness of the palm. A: Photograph of the palm, indicating where the THz 

measurements were taken; B: A b-scan image showing the variation in stratum 

corneum thickness with palm position. The white dashed line indicates the 

interface between the quartz window and the stratum corneum; and the black 

dashed line indicates the interface between the stratum corneum and the epidermis. 

The grey bar represents the ratio of the electric field at a given optical 

delay, t, over the maximum electric field [E(t)/Emax]. 

is shown in Figure 11. For comparison the measurement 

of the palm alone is also plotted. In the figure, there are 2 

troughs, which correspond to the top and bottom surface 

of the stratum corneum. The optical delay between them 

can be used to calculate the thickness of this layer. These 

results show that THz light is able to penetrate through 

wound dressings with only slight attenuation to reveal 

the skin depth information. This therefore indicates that 

THz imaging is likely to be able to detect and measure 

changes to the stratum corneum and epidermis which 

could for example, be caused by burns. To illustrate how 

sensitive THz imaging is to the stratum corneum, we have 

also imaged the side of a healthy hand. As the position 

of the measurement changes, as indicated by the arrow in 

Figure 12A, the optical delay between the reflections from 

the top and bottom of the stratum corneum increases. This 

is because the stratum corneum is thicker at the tip of the 

arrow than at the arrow foot. By plotting the reflected amplitude 

intensity against position we obtain the depth profile 

image of the palm in Figure 12B. By using frequency 

and wavelet domain deconvolution we are able to resolve 

thinner layers of skin than if basic deconvolution is used [73] . 


1.0 

0.5 

0.0 

-0.5 

-1.0 


COMPARISON WITH OTHER 

TECHNOLOGIES 

Numerous groups have investigated direct transmission 

or reflection THz imaging as a means of distinguishing 

tissue types [30,55,74] and recognizing diseases including 

tumors penetrating below the surface layers of skin or 

into organs [56,58,75] . Although progress is being made, the 

competition from other more developed imaging modalities 

is fierce. Optical coherence tomography, ultrasound, 

near-IR, and Raman spectroscopy, MRI, positron emission 

tomography, in situ confocal microscopy, and X-ray 

techniques have all received much more attention and 

currently offer enhanced resolution, greater penetration, 

higher acquisition speeds, and specifically targeted contrast 

mechanisms. This does not preclude THz imaging 

from finding a niche in this barrage of already favorable 

modalities. There is still no technique that can readily distinguish 

benign from malignant lesions macroscopically 

at the surface or subdermally. The sensitivity of THz signals 

to skin moisture, which is often a key indictor, is very 

high, and competing techniques such as high-resolution 

MRI are less convenient and more costly. 

The resolution of ordinary THz imaging is diffraction 

limited, however, its high sensitivity to water content and 

great surface imaging capability provide motivation for further 

development and sub-wavelength resolution has been 

achieved in near-field studies [76] . Indeed shallow subsurface 

images can be very revealing and the first few hundred 

micrometers are hard to image with other modalities. The 

high sensitivity of THz radiation to fluid composition and 

the variable conductivity in tissue [77] is likely to lead to statistically 

significant differences between nominally identical 

samples taken at different locations in the body at different 

times or from different subjects. This may ultimately prove 

advantageous; however, in the short term, it will tend to 

mask sought for differences that are indicative of diseases. 

CONCLUSION 

THz imaging is still in its early stage of development, but 

as this paper has shown, has great potential to be a valuable 

imaging technique in the future. In the past decade, 

THz imaging applications in biomedical fields have drawn 

extensive interest and advancements in imaging methods 

and theoretical analysis continue to enable further applications 

to be investigated. 

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S- Editor Cheng JX L- Editor Webster JR E- Editor Zheng XM 


W J R 



doi:10.4329/wjr.v3.i3.66 

Applications of new irradiation modalities in patients with 

lymphoma: Promises and uncertainties 

Youlia M Kirova, Cyrus Chargari 

Youlia M Kirova, Cyrus Chargari, Department of Radiation 

Oncology, Institut Curie 26, rue d’Ulm, 75248 Paris, Cedex 05, 

France 

Author contributions: Kirova YM designed the study; Kirova 

YM and Chargari C wrote the paper. 

Correspondence to: Youlia M Kirova, MD, Department of 

Radiation Oncology, Institut Curie 26, rue d’Ulm, 75248 Paris, 

Cedex 05, France. youlia.kirova@curie.net 

Telephone: +33-1-44324193 Fax: +33-1-53102653 

Received: January 15, 2011 Revised: March 2, 2011 

Accepted: March 9, 2011 


Abstract 

New highly conformal irradiation modalities have emerged 

for treatment of Hodgkin lymphoma. Helical Tomotherapy 

offers both intensity-modulated irradiation and accurate 

patient positioning and was shown to significantly decrease 

radiation doses to the critical organs. Here we review 

some of the most promising applications of helical 

tomotherapy in Hodgkin disease. By decreasing doses to 

the heart or the breast, helical tomotherapy might decrease 

the risk of long-term cardiac toxicity or secondary 

breast cancers, which are major concerns in patients 

receiving chest radiotherapy. Other strategies, such as 

debulking radiotherapy prior to stem cell transplantation 

or total lymphoid irradiation may be clinically relevant. 

However, helical tomotherapy may also increase the volume 

of tissues that receive lower doses, which has been 

implicated in the carcinogenesis process. Prospective 

assessments of these new irradiation modalities of helical 

tomotherapy are required to confirm the potential 

benefits of highly conformal therapies applied to hematological 

malignancies. 


Key words: Hodgkin lymphoma; Helical tomotherapy; 

Cardiac toxicity; Secondary cancers 

Peer reviewer: Ying Xiao, PhD, Professor, Director, Medical 



Radiology 

Physics, Department of Radiation Oncology, Thomas Jefferson 

University Hospital, Philadelphia, PA 19107-5097, United States 

Kirova YM, Chargari C. Applications of new irradiation modalities 

in patients with lymphoma: Promises and uncertainties. 

World J Radiol 2011; 3(3): 66-69 Available from: URL: http:// 

www.wjgnet.com/1949-8470/full/v3/i3/66.htm DOI: http:// 

dx.doi.org/10.4329/wjr.v3.i3.66 

INTRODUCTION 

Radiation therapy still plays a major role in the management 

of hematological malignancies. Its place and modalities 

for treatment of lymphoma have evolved over recent 

decades. First, randomized studies supported reduction 

of field size and dose radiation in treatment programs for 

Hodgkin disease [1] . These developments were encouraged 

by reports that mediastinal radiotherapy was associated 

with cardiac toxicity and second malignancies, particularly 

when chemotherapy agents were used concomitantly or 

sequentially. Second, sophisticated imaging technologies 

and new radiation delivery techniques have become available 

[2] . With the recent advances in irradiation devices, new 

intensity modulated irradiation modalities have emerged. 

Those offer both increased target dose conformality and 

improved normal tissue avoidance. Helical tomotherapy 

combines inversely planned intensity modulated radiotherapy 

(IMRT) with on-board megavoltage imaging 

devices [3] . In this way, it has become possible to tailor very 

sharp dose distributions around the target volumes, close 

to critical organs [4] . It has emerged as one of the most 

promising techniques for IMRT delivery. 

Here we summarize some of the most promising applications 

of helical tomotherapy in patients with hematological 

malignancies. 

CLINICAL APPLICATIONS 




REVIEW 

For lymphoma irradiation, it is now the standard of care 


to use involved-field radiotherapy rather than the extended 

radiation fields of the past [5] . In this setting of volume 

reduction, implementation of new strategies aimed at 

further improving target coverage is promising. Helical 

tomotherapy combines inversely planned IMRT with 

on-board megavoltage imaging devices [3] . In this way, it 

has become possible to tailor very sharp dose distributions 

around the target volumes, close to critical organs. 

Improving dose conformality around the volumes has 

become an important end-point for radiation oncologists. 

Dosimetric results from planning studies of helical tomotherapy 

have demonstrated its ability in better sparing 

critical organs from irradiation, in comparison with more 

conventional irradiation modalities. Helical tomotherapy 

was shown to provide similar target coverage, and to 

improve both dose conformality and dose homogeneity 

within the target volume. This modern irradiation 

device allows accurate repositioning and critical organs 

visualization. Tomita et al [6] compared radiation treatment 

plans that used IMRT with helical tomotherapy or threedimensional 

conformal radiation therapy for nasal natural 

killer/T-cell lymphoma. Authors found that IMRT 

achieved significantly better coverage of the planning 

target volume (PTV), with more than 99% of the PTV 

receiving 90% of the prescribed dose, whereas 3D-CRT 

could not provide adequate coverage of the PTV, with 

only 90.0% receiving 90% (P < 0.0001). These results 

and others demonstrated that helical tomotherapy could 

significantly improve target coverage when the PTV was 

close to critical organs. 

Prospective data with long-term follow-up evidenced 

that heart dose exposure may cause cardiac disease and 

adversely affect quality of life, particularly in young patients 

with mediastinal radiotherapy for Hodgkin lymphoma. 

Hudson et al [7] assessed the impact of treatment 

toxicity on long-term survival in pediatric Hodgkin’s 

disease, and reported an excess mortality from cardiac disease 

in survivors of pediatric Hodgkin’s disease (22, 95% 

CI: 8-48), compared with age- and sex-matched control 

populations. Cardiac irradiation contributes to this excess 

of risk [8] . Recent data reported that helical tomotherapy 

could decrease radiation dose exposure for breasts, lung, 

heart and thyroid gland in patients treated for advanced 

Hodgkin’s disease [9] . 

Since radiation-induced cardiovascular pathology 

is a major concern in patients undergoing therapeutic 

chest irradiation, helical tomotherapy has been logically 

investigated for improving heart avoidance. The physiopathology 

and manifestations of radiation-induced heart 

disease may considerably vary according to the dose, 

volume and technique of irradiation, and every effort 

should be made to avoid irradiating cardiac structures [10] . 

In this way, it will be possible to substantially decrease 

the risk of death from ischemic heart disease associated 

with radiation, which is particularly significant in patients 

receiving other cardiotoxic agents, such as anthracyclines. 

Actually, helical tomotherapy also allows treatments 

that would be difficult for conventional radiotherapy 


Kirova YM et al . Modern radiotherapy of lymphomas 

machines to deliver, such as treating mediastinal lymph 

nodes [11] . Figure 1 shows the distribution dose during radiotherapy 

of a patient who was diagnosed with multiple 

pleural and mediastinal locations from lymphoma. Dosevolumes 

histograms evidence accurate sparing of some 

organs at risk, with the possibility to treat multiple targets 

simultaneously. 

Several other promising applications for helical tomotherapy 

have emerged. These strategies include treatment 

of patients who are at high risk of radiation-induced toxicity 

because of individual susceptibility, such as patients 

with acquired immunodeficiency [12] . Helical tomotherapy 

could also be used for decreasing the doses to critical 

structures in patients treated with concurrent targeted 

agents, which might potentially increase the risk of side 

effects [13] . Moreover, it permits re-irradiation of relapsed 

disease, a setting that considerably increases the risk of 

consequent delayed toxicity. Introducing helical tomotherapy 

to the field of lymphoma may also provide safer 

and more accurate radiotherapy to selected patients with 

bulky residual disease [1] . We previously reported the feasibility 

of helical tomotherapy to decrease the acute toxicity 

of debulking irradiation before allograft in patients 

with refractory lymphoma. In other malignancies, our 

retrospective data in patients with solitary plasmocytoma 

demonstrated that doses to critical organs, including the 

heart, lungs, or kidneys could be decreased [14] . This may 

be clinically relevant in heavily pretreated patients who 

are at risk for subsequent treatment-related cardiac toxicity. 

High response rates were also reported and encouraged 

further prospective assessment, and most patients 

experienced a complete response prior to stem cell allograft. 

An increased risk of secondary malignancies has been 

reported after radiotherapy for lymphoma. In particular, 

young patients have a high risk of developing breast cancer 

in their life after mediastinal radiotherapy for a lymphoma 

[15] . The improved outcome among patients with 

Hodgkin’s lymphoma has been associated with increased 

incidence of second malignancies. This risk becomes 

significantly elevated 5 to 10 years after irradiation for 

Hodgkin lymphoma [16,17] and the incidence of breast cancer 

has been reported to increase by a factor of 4.3 (95% 

CI: 2.0-8.4) for patients treated with mantle irradiation [18] . 

Koh et al [19] quantified the reduction in radiation dose to 

normal tissues and modeled the reduction in secondary 

breast cancer risk, and suggested significant relative 

risk reduction for second cancers with involved field 

radiotherapy. While the dose response for radiation dose 

above 10 Gy remains uncertain, carcinogenesis after radiation 

is exacerbated by the large dose gradient across the 

breast and treatment field position [20] . Although helical 

tomotherapy might significantly decrease high doses delivered 

to the breast, it increases the volume that receives 

lower doses, which has also been implicated in the carcinogenesis 

process. For that reason, intensity-modulated 

irradiation should not be delivered in children outside of 

a clinical trial. 


proton therapy is very low and only a few patients could 

benefit from this highly conformal irradiation modality. 

CONCLUSION 

There is growing dosimetric evidence that highly conformal 

irradiation modalities may improve critical organs 

sparing, with clinically relevant consequences. Prospective 

clinical evaluation of helical tomotherapy modalities is 

required to confirm the potential benefits of highly conformal 

therapies applied to hematological malignancies. 

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lymphoma patients: conventional radiotherapy, intensitymodulated 

radiotherapy, and three-dimensional proton radiotherapy. 

Int J Radiat Oncol Biol Phys 2009; 75: 1173-1180 

S- Editor Cheng JX L- Editor O’Neill M E- Editor Zheng XM 


W J R 



doi:10.4329/wjr.v3.i3.70 

Estimation of intra-operator variability in perfusion 

parameter measurements using DCE-US 

Marianne Gauthier, Ingrid Leguerney, Jessie Thalmensi, Mohamed Chebil, Sarah Parisot, Pierre Peronneau, 

Alain Roche, Nathalie Lassau 

Marianne Gauthier, Ingrid Leguerney, Jessie Thalmensi, 

Sarah Parisot, Pierre Peronneau, Alain Roche, Nathalie 

Lassau, IR4M, UMR 8081, CNRS, Paris-Sud 11 Univ, Gustave 

Roussy Institute, Villejuif 94805, France 

Mohamed Chebil, Nathalie Lassau, Department of Imaging, 

Ultrasonography Unit, Gustave Roussy Institute, Villejuif 

94805, France 

Author contributions: Gauthier M performed the majority 

of experiments, designed the study and wrote the manuscript; 

Leguerney I was involved in analyzing results and editing the 

manuscript; Thalmensi J, Parisot S and Peronneau P provided 

substantial contributions to conception and design, acquisition 

of data, analysis, and interpretation of the data; Chebil M was 

involved in the design of the study; Roche A supervised the 

project; Lassau N managed each step of the study, provided 

contribution to data analyses and was involved in editing the 

manuscript. 

Correspondence to: Marianne Gauthier, MSc, IR4M, UMR 

8081, CNRS, Paris-Sud 11 Univ, Gustave Roussy Institute, 

Villejuif 94805, France. marianne.gauthier@igr.fr 

Telephone: +33-1-42116215 Fax: +33-1-42115495 

Received: December 24, 2010 Revised: March 2, 2011 

Accepted: March 9, 2011 


Abstract 

AIM: To investigate intra-operator variability of semiquantitative 

perfusion parameters using dynamic contrast-enhanced 

ultrasonography (DCE-US), following 

bolus injections of SonoVue ® . 

METHODS: The in vitro experiments were conducted 

using three in-house sets up based on pumping a fluid 

through a phantom placed in a water tank. In the in vivo 

experiments, B16F10 melanoma cells were xenografted 

to five nude mice. Both in vitro and in vivo , images 

were acquired following bolus injections of the ultrasound 

contrast agent SonoVue ® (Bracco, Milan, Italy) 

and using a Toshiba Aplio ® ultrasound scanner connected 

to a 2.9-5.8 MHz linear transducer (PZT, PLT 604AT 



Radiology 

probe) (Toshiba, Japan) allowing harmonic imaging 

(“Vascular Recognition Imaging”) involving linear raw 

data. A mathematical model based on the dye-dilution 

theory was developed by the Gustave Roussy Institute, 

Villejuif, France and used to evaluate seven perfusion 

parameters from time-intensity curves. Intra-operator 

variability analyses were based on determining perfusion 

parameter coefficients of variation (CV). 

RESULTS: In vitro , different volumes of SonoVue ® 

were tested with the three phantoms: intra-operator 

variability was found to range from 2.33% to 23.72%. 

In vivo , experiments were performed on tumor tissues 

and perfusion parameters exhibited values ranging 

from 1.48% to 29.97%. In addition, the area under the 

curve (AUC) and the area under the wash-out (AUWO) 

were two of the parameters of great interest since 

throughout in vitro and in vivo experiments their variability 

was lower than 15.79%. 

CONCLUSION: AUC and AUWO appear to be the most 

reliable parameters for assessing tumor perfusion using 

DCE-US as they exhibited the lowest CV values. 





ORIGINAL ARTICLE 

Key words: Dynamic contrast-enhanced ultrasonography; 

Intra-operator variability; Functional imaging; Semi-quantitative 

perfusion parameters; Linear raw data; Quantification 

Peer reviewers: Chan Kyo Kim, MD, Assistant Professor, Department 

of Radiology, Samsung Medical Center, Sungkyunkwan 

University School of Medicine, 50 Ilwon-dong, Kangnamgu, 

Seoul 135-710, South Korea; Sergio Casciaro, PhD, Institute 

of Clinical Physiology - National Research Council,Campus 

Universitario Ecotekne, Via Monteroni, 73100 Lecce, Italy 

Gauthier M, Leguerney I, Thalmensi J, Chebil M, Parisot S, 

Peronneau P, Roche A, Lassau N. Estimation of intra-operator 

variability in perfusion parameter measurements using DCE- 


US. World J Radiol 2011; 3(3): 70-81 Available from: URL: 

http://www.wjgnet.com/1949-8470/full/v3/i3/70.htm DOI: 

http://dx.doi.org/10.4329/wjr.v3.i3.70 

INTRODUCTION 

Tumor angiogenesis is a process involving the proliferation 

of new blood vessels which penetrate tumors supplying 

them with nutrients and oxygen [1,2] . Nowadays, research 

is focused on the development of anti-angiogenic 

treatments whose aim is to destroy neoblood vessels 

which often occur initially without any morphological 

changes [3,4] . 

Until now, treatment evaluation has been based on 

Response Evaluation Criteria in Solid Tumors (RECIST) [5] . 

Even though RECIST criteria were recently revised, they 

still only concern morphological information [6] . It is commonly 

recognized that this criterion is no longer optimal 

for the early assessment of anti-angiogenic treatments 

which primarily target microvascularization. Functional 

imaging is currently establishing itself as the best modality 

for evaluating such therapies, by determining a series of 

semi-quantitative perfusion parameters related to tumor 

perfusion. These were defined as semi-quantitative as they 

only provided a relative evaluation of the physiological 

parameters such as blood flow or blood volume based on 

the dye dilution theory. 

Nowadays, dynamic contrast-enhanced ultrasonography 

(DCE-US) is becoming increasingly widespread [7,8] as 

it allows functional imaging [9,10] . However, one of its major 

drawbacks is its intra-operator variability which could 

have a major impact on measurements, leading to erroneous 

interpretations. A small difference in perfusion could 

be interpreted as a functional change but might simply be 

due to operator variability. 

Until now, information on intra-operator variability has 

been lacking. Consequently, the purpose of our study was 

to evaluate the intra-operator variability of semi-quantitative 

perfusion parameter measurements using DCE-US, 

both in vitro and in vivo, following bolus injections of SonoVue 

® (Bracco, Milan, Italy). 

MATERIALS AND METHODS 

Contrast agents 

DCE-US studies were performed using bolus injections 

of SonoVue ® , a second generation contrast agent, consisting 

of microbubbles of sulphur hexafluoride (SF6) 

stabilized by a shell of amphiphilic phospholipids [11,12] . 

The SF6 gas does not interact with any other molecules 

found in the body as it is a very inert gas. The size of the 

microbubbles, ranging from 1 to 10 μm [12] , allows them 

to circulate through the whole blood volume. In addition, 

SonoVue ® is a purely intravascular contrast agent which 

makes it ideal for the evaluation of perfusion [12] . Insonated 

at low acoustic power, SonoVue ® , whose nonlinear 

harmonic response is high [13] , provides continuous real- 


Gauthier M et al . Variability of perfusion parameters using DCE-US 

time ultrasonographic (US) imaging without destroying 

the microbubbles [14] . 

Before any US exam, the contrast agent was reconstituted 

by introducing 5 mL of 0.9% sodium chloride into 

the vial, containing a pyrogen-free lyophilized product, 

followed by manual shaking for at least 20 s. One experiment 

involved several injections of SonoVue ® . As the 

microbubbles tended to accumulate at the upper surface 

because of buoyancy, the preparation was systematically 

manually checked before each injection in order to recover 

the required homogeneous solution. Each experiment 

lasted less than 2 h on account of the stability of SonoVue 

® over time which is 6 h after its reconstitution [11] . 

Time-intensity method 

The time intensity method is essentially based on the dye 

dilution theory: after the injection of the indicators, contrast 

agent concentration is monitored as a function of 

time, generating a time intensity curve (TIC) from which 

a series of semi-quantitative perfusion parameters is extracted 

and analyzed [15,16] . To be valid, a series of assumptions 

must be verified [17] : (1) Flow has to be constant so 

that the amount of microbubbles injected has no effect 

on the flux; (2) Blood and contrast agent must be adequately 

mixed to obtain a homogeneous concentration; 

(3) Recirculation should not interfere with the first pass; 

and (4) The mixing of the contrast agent must exhibit 

linearity and a stable condition [18] . Linearity refers to the 

linear relationship between bubble concentration and signal 

intensity and was previously confirmed for low doses 

by Greis [12] as well as by Lampaskis et al [19] in the context 

of bolus injection. 

In our study, conditions were assumed to be satisfied. 

The semi-quantitative perfusion parameters that we analyzed 

were therefore directly extracted from the TIC. 

In vitro studies 

US protocol: SonoVue ® bolus injections were performed 

through a 1-mL syringe (Terumo ® , Belgium) and a 

“26Gx1/2” needle (Terumo ® , Belgium). The injection 

site was marked so that the same site was used for all the 

in vitro studies. It was positioned at a distance of 30 cm 

from the input of the phantom. 

According to the Guidelines for Evaluating and Expressing 

the Uncertainty of NIST (National Institute of 

Standards and Technology) Measurements Results, intraoperator 

variability studies must be performed under the 

following conditions: (1) The same measurement procedure; 

(2) The same observer; (3) The same measuring instrument, 

used under the same conditions; (4) The same 

location; and (5) Repetition over a short period of time. 

Thus, all the experimental conditions as well as the 

operators injecting the SonoVue ® and manipulating the 

ultrasound scanner were the same for all acquisitions. 

To minimize errors which might have been due to 

possible SonoVue ® residues in the injection materials, a 

new syringe and a new needle were used for each injection. 

In addition, the circuit was entirely emptied, rinsed 



6 

3 

4 

Figure 1 Schematic diagram of the closed-circuit. No contact with ambient 

air was possible. In addition, as water was degassed, no significant amount of 

gas was trapped in the circuit. Based on the same set-up, three phantoms were 

used throughout the in vitro experiments: (a) a single straight pipe phantom; (b) 

a three intertwined pipe phantom; (c) a dialyzer. The Gustave Roussy Institute 

(IGR) ratio was tested throughout the in vitro experiments as it corresponded 

to the ratio (4.8 mL per patient) previously validated and routinely used at the 

IGR. 1: Peristaltic pump; 2: Syringe; 3: PZT, PLT 604AT probe; 4: Phantom; 5: 

Custom-made water tank; 6: Reservoir; 7: Tubing (silicone pipe; internal diameter: 

2 mm; wall thickness: 1 mm). 

and reset with degassed water between each acquisition. 

Thus, no contrast agent residues were present in the circuit 

so that the initial conditions were exactly the same 

for all the experiments. 

The three phantoms consisted of a closed-circuit flow 

model as no contact with ambient air was possible. Consequently, 

as the water was degassed and the circuit was 

closed, no significant amount of gas was trapped in the 

set-up (Figure 1). 

Images were acquired using a Toshiba Aplio ® ultrasound 

scanner (Toshiba, Japan) version 6, release 5, connected 

to a 2.9-5.8 MHz linear transducer (PZT, PLT 

604AT probe). Harmonic imaging was performed using 

the “Vascular Recognition Imaging” (VRI) mode combining: 

(1) Fundamental B mode imaging, which allows 

simultaneous but independent grey scale visualization of 

morphological structures; (2) Doppler imaging, which 

provides vascular information; and (3) Harmonic imaging, 

based on the pulse inversion mode, which consists 

of summing echoes resulting from two waves which are 

inverted copies of each other. As microbubbles exhibit 

non-linear responses, the resulting sum of the echoes will 

be different from 0 implying a non-null signal [20] . 

Acquisitions lasting 50 s were obtained at a low mechanical 

index (MI = 0.1) and at a rate of 5 frames per second 

(fps). 

Single straight pipe phantom: The first assembly consisted 

of a single straight silicone pipe phantom, immersed 

in a custom-made water tank which was connected to a 

peristaltic pump (SP vario/PD 5101, Heidolph ® , Germany) 

providing a defined water flow rate of 42.4 mL/min. 

This phantom was used to mimic blood flow. Tubing was 

made of a 1 mm thick silicone pipe with a 2 mm internal 

diameter. A custom-made probe holder was used to keep 

the probe still throughout the experiments. 

A region of interest (ROI) was set in the upper part 


5 

7 

2 

1 

B 

7.6 

A 

Power (a.u.) 

140 

120 

100 

80 

60 

40 

20 

0 

0 20 40 

t/s 

1 

5 fps 

VRh5.8 

9.2 

MI 0.1 

Linear raw data 

Figure 2 Single straight pipe phantom. A: Image extracted from an acquisition 

obtained after the bolus injection of SonoVue ® . Harmonic imaging was 

done based on the Vascular Recognition Imaging mode. The region of interest 

was set in the upper part of the pipe. Each acquisition involved a new manually 

drawn region of interest. Once the region of interest was selected, the ultrasound 

scanner directly allowed access to the time intensity curve associated 

with the selected region of interest. The linear raw data to be modeled were 

converted through text files generated by the ultrasound scanner and extracted 

to obtain a graph using Excel ® ; B: The graph displays the Excel ® curve to be fitted 

and analyzed in order to obtain the perfusion parameters. 

of the pipe (Figure 2A). Each injection involved a new 

ROI and its associated TIC (Figure 2B). Three volumes 

of SonoVue ® were tested. The first experiment involved 

five 0.02 mL bolus injections of contrast agent for a 

total amount of water set at 50 mL in the closed-circuit. 

This ratio respected that granted by marketing approval 

(“Autorisation de Mise sur le Marché”: AMM) (2.4 mL of 

SonoVue ® for 5 L of blood). The second experiment was 

performed by injecting five times a 0.05 mL bolus of SonoVue 

® . This volume involved a ratio routinely used for 

clinical exams (4.8 mL of SonoVue ® for 5 L of blood) 

and particularly in four studies performed at the Gustave 

Roussy Institute (IGR), involving 117 patients and 823 

DCE-US exams [21,22] as well as a national project supported 

by the “Institut National du Cancer” (French National 

Cancer Institute) [23] . The last experiment involved five 

0.08 mL bolus injections of SonoVue ® . As the phantom 

became more complex, we focused on the IGR ratio previously 

validated in IGR studies. 

Three intertwined pipe phantom: A second phantom 

consisted of three intertwined silicone pipes immersed in 

a custom-made water tank. Two of the three tubes were 


6.9 

B 

C 

A 

Power (a.u.) 

6000 

4500 

3000 

1500 

0 

in silicone with an internal diameter of 2 mm and a 1 mm 

thick wall as in the case of the previous phantom. The 

third one, originating from a catheter (Surflo ® winged infusion 

set, Terumo ® , Belgium), had a 1 mm internal diameter 

and a 0.5 mm thick wall. The input and the output of 

the phantom were composed of three-way taps (Discofix ® , 

B. Braun, Melsungen, Germany) allowing linkage between 

the three pipes (Figure 3A). The phantom was connected 

to the same pump as previously described, providing a 

defined water flow rate set at 42.4 mL/min. Such an as- 


1 

0 5 10 15 20 

t /s 


5 fps 

VRh5.8 

9.2 

MI 0.1 

Figure 3 Three intertwined pipe phantom. A: Picture of the phantom: three 

pipes (2 pipes with a 2 mm internal diameter and a 1 mm thick wall, 1 pipe with 

a 1 mm internal diameter and a 0.5 mm thick wall ) were intertwined to mimic a 

complex structure akin to that of vessels in the microvascularization; B: Image 

extracted from an acquisition obtained after a bolus injection of SonoVue ® . As 

in the case of the first phantom, harmonic imaging was based on the Vascular 

Recognition Imaging mode. The region of interest contained both pipes and 

water and was manually drawn for each of the five injections; C: Based on the 

selected region of interest, the ultrasound scanner provided the time intensity 

curve converted through text files. These were used to display the associated 

Excel ® curve to be analyzed. 


sembly was designed to mimic a complex structure akin to 

that of vessels in tumors. 

A new ROI containing both pipes and water spaces 

(Figure 3B), was drawn for each injection and the associated 

TIC was obtained (Figure 3C). The total amount 

of water in the circuit was set at 60 mL. Two series of 

acquisitions were obtained involving, respectively, five 

0.03 mL (AMM ratio) and 0.06 mL (IGR ratio) bolus injections 

of contrast agent. 

Dialyzer: The third assembly was composed of a dialyzer 

(FX PAED, Fresenius Medical Care, France). The dialysis 

cartridge, consisting of about 1550 capillaries with an 

internal diameter of 220 μm, was connected to the peristaltic 

pump providing a water flow rate of 42.4 mL/min 

and was immersed in water. To minimize attenuation due 

to the original plastic case of the dialyzer, a rectangular 

part of it was removed and replaced by a cellophane sheet 

to maintain the circuit closed [24] . The advantage of such a 

phantom was that the capillaries of the dialyzer were comparable 

in dimension to that of one type of vessel found 

in the microvascularization (arteriole diameter < 300 μm). 

In addition, as the size of SonoVue ® microbubbles ranged 

from 1 to 10 μm [12] , they were about a thousand-fold the 

dimensions of capillary pores (2.4 nm), thus ensuring the 

intravascular property of the ultrasound contrast agent. 

As shown in Figure 4A, attenuation occurs in the lower 

part of the dialyzer: it is characterized by a strong decrease 

in amplitude and a loss of the contrast signal. An 

ROI was drawn for each of the repeated measurements 

and only contained the upper part of the dialyzer so that 

the acquisition was not prone to attenuation phenomena 

[25] . Based on the selected ROI, the associated time 

intensity curve was obtained for the analysis (Figure 4B). 

The total amount of water was 100 mL and a volume of 

0.10 mL of SonoVue ® was tested five times (IGR ratio). 

In vivo studies 

Animals and tumor model: Experiments were conducted 

with nude female mice aged from 6 to 8 wk with the 

approval of the European Convention for the Protection 

of Vertebrate Animals used for experimental and other 

scientific purposes (Strasbourg, 18.III.1986; text amended 

according to the provisions of protocol ETS No. 170 as 

of its entry into force on 2nd December 2005). 

The selected tumor model was the B16F10 (CRL-6475, 

ATCC, American Type Culture Collection) melanoma cell 

line which is a murine skin cancer. The tumor cells were 

cultured in DMEM (Dulbecco minimum essential medium) 

(Gibco Life Technologies, France) combined with 

10% fetal bovine serum, 1% penicillin/streptomycin and 

glutamate (Invitrogen Life Technologies, Inc., France) 

to avoid bacterial contamination of the solution. While 

growing, cells were maintained in an incubator at 37℃. 

Tumors were xenografted onto the right flank of five 

mice (Figure 5A) through a subcutaneous injection of 2 

× 10 6 melanoma cells in 0.2 mL of Phosphate Buffered 

Saline (PBS). DCE-US exams were performed following 

three 0.02 mL, 0.05 mL or 0.1 mL retro-orbital bolus 


B 

Power (a.u.) 

7.6 

A 


Attenuated part 

1030 

930 

830 

730 

630 

530 

430 

0 10 20 30 40 

t /s 

injections of SonoVue ® according to the methodology 

used in our lab. 

Settings: During the experiments, mice were placed on 

the left flank and maintained at a constant temperature 

through a warming pad (TEM, Bordeaux, France) connected 

to a Gaymar T/Pump ® (Gaymar Industries, Inc., 

USA). The temperature was regulated with the adjustable 

thermostat of the pump and was set at 40°C (internal 

mouse temperature: 39℃). Each mouse was weighed and 

the tumor volume was determined before each DCE- 

US exam. The ROI was set to exclusively include the 

tumor (Figure 5B-C). An ROI was drawn for each of 

the repeated measurements and once it was selected, the 

ultrasound scanner directly allowed access to the time intensity 

curve associated with the selected ROI. The linear 

raw data to be modeled were converted through text files 

and extracted to obtain a graph using Excel ® (Figure 5D). 

A break of at least 15 min was observed between each 

injection in addition to 3 min of insonation at a high 

mechanical index (MI = 1.4), so that contrast agent could 

be eliminated. Mice were kept asleep no more than 2 h. 

This duration included the time required for the mice to 

obtain a stationary heart rate after the administration of 

anesthesia, acquisition time and the duration of the break 


5 fps 

VRh5.8 

9.2 

MI 0.1 


Figure 4 Dialyzer. A: Image extracted from an acquisition obtained after a 

bolus injection of SonoVue ® . As in the case of the first two phantoms, harmonic 

imaging was based on the Vascular Recognition Imaging mode. The region of 

interest contained the upper part of the dialyzer to avoid attenuation phenomena 

in the lower parts. This was manually drawn for each injection; B: To determine 

perfusion parameters from the time intensity curve obtained following the 

selection of the region of interest, this was converted through text files so that 

the analysis could be performed using the Solver program in Excel ® . 

between each injection. Three injections per mouse were 

considered for the data analysis. Mice underwent either 

chemical or gaseous anesthesia. 

Chemical anesthesia: The amount of chemical anesthesia 

was determined based upon mouse body weight. Once 

weighed, the required amount of anesthesia was prepared 

and injected intraperitoneally using the 1-mL syringe and a 

“30Gx1/2” needle (Microlance, Ireland). The solution 

consisted of ketamine (10 mg/mL, Ketalar ® , Parapharm, 

France) and xylazine (2%, Rompun ® , Bayer, France). To 

ensure that the mice remained asleep throughout the 

experiment, 150 µL/g per mouse were systematically injected. 

Gaseous anesthesia: Mice were anaesthetized through 

a 2 L/min inhalation of O2 combined with 2.5% of isoflurane. 

It was possible to modify the flow rate during the 

experiment so that mice could be maintained asleep without 

being endangered throughout the experiment. 

US protocol: Preliminary fundamental B-mode imaging 

using a 14 MHz PLT 1204AT (Toshiba, Japan) probe 

was performed to determine the tumor volume prior to 

the SonoVue ® injection (Figure 5B). The largest longitudinal 

and transversal sections allowed us to determine 

the tumor volume by measuring the three perpendicular 

tumor diameters [26] according to the following formula: 

V = 1/2 × (depth × width × length). 

Harmonic imaging was performed in the same way 

as for the in vitro experiments with a mechanical index set 

at 0.1 and a rate of 5 fps. Acquisitions lasting 3 min were 

recorded allowing visualization of both the wash-in and 

wash-out parts of the TICs. 

Data analysis 

As already described in the literature, linear raw data (uncompressed 

linear data obtained before standard videovisualization) 

have the advantage of exhibiting a linear 

dynamic range which is the essential part of the evaluation 

of semi-quantitative perfusion parameters from 

TICs [27] . Acquisitions involved recording harmonic images 

after the SonoVue ® injection, using dedicated software, 

CHI-Q ® , on the Toshiba Aplio ® ultrasound scanner. In 

a manually outlined ROI, the mean US signal intensity 

induced by contrast uptake was obtained and expressed 

in arbitrary units. This was linearly linked to the number 

and size of microbubbles in the ROI (Aplio ® procedure) 

[28,29] . Then, the corresponding TIC to be modeled 

was converted through text files generated by the ultrasound 

scanner and extracted to obtain a graph using Excel 

® . Seven semi-quantitative perfusion parameters were 

extracted from this curve: the peak intensity (PI) was the 

difference between Vmax [maximal intensity value: V(Tmax)] 

and V0 [Initial intensity value: V(T0)] and represented the 

highest intensity value attained by the TIC for the defined 

ROI. The time to peak intensity (TPI), corresponding 

to Time to Peak Intensity, was the time required for the 

contrast agent to arrive in the tumor and reach the PI. It 


D 

A 

Power (a.u.) 

140 

120 

100 

80 

60 

40 

20 

0 

0 20 40 60 80 100 120 

t /s 

corresponded to the difference between the latency time 

(TL), defined as the time between the injection of the 

product and the beginning of contrast uptake, and Tmax. 

From a mathematical point of view, TL corresponded to 

the time at the intersection between y=V0 and the tangent 

at Tmax/2. The AUC, AUWI and AUWO corresponded to 

the area under the curve, the area under the wash-in (from 

T0 to Tmax) and the area under the wash-out (from Tmax to 

Tend corresponding to the end of the acquisition) of the 

TIC. The area calculations were based on the trapezoidal 

rule: the region under the graph of the fitted curve was 

approximated by trapezoids whose areas were calculated 

to provide approximations of the areas under the curve, 

the wash-in or the wash-out. An additional operation of 

subtracting the offset on the y-axis was performed so that 

the total area under the curve was independent of it. The 

limits of integration were defined as follows: 

[ 0 ] , X ∈ T Tend 

Where T0 is the initial time. The slope coefficient of 

the wash-in (WI) was literally defined as the slope of the 

tangent of the wash-in at half maximum. Finally, the 

full-width at half maximum (FWHM) was defined as the 

time interval during which the value of the intensity was 

higher than Vmax/2. This parameter is commonly considered 

as a first approximation of the mean transit time 

(MTT) (Figure 6) [8,26,30] . However, as the linear raw data 

provided by the ultrasound scanner were too noisy, ex- 


B 


9.11 mm 

12.18 mm 


7.6 

C 

traction was performed after TIC fitting. This was based 

on the mathematical model developed at the IGR (Patent: 

WO/2008/053268 entitled “Method and system for 

quantification of tumoral vascularization”). 

p 

⎛ ⎞ 

5 fps 

VRh5.8 

9.2 

Figure 5 In vivo. A: Experiments were conducted with nude female mice aged from 6 to 8 wk. The selected tumor model was the B16F10 melanoma cell line which 

is a murine skin cancer; B, C: The region of interest contained only the tumor and was drawn for each injection performed. If the image was not well defined using the 

harmonic mode, the B-mode image was used to correctly define the region of interest; D: As in the case of the in vitro experiments, the ultrasound scanner displayed 

the associated time intensity curve. This was extracted and converted through an Excel ® file so that the analysis could be performed to obtain the required perfusion 

parameters. 

MI 0.1 

⎛ t ⎞ 

⎜ A + ⎜ ⎟ ⎟ 

⎜ a2 

⎟ 

I( t) = a0 + ( a1 − a0 

) ∗ 

⎝ ⎠ 

⎜ q ⎟ 

⎜ ⎛ t ⎞ 

B ⎟ 

⎜ 

+ ⎜ ⎟ 

a ⎟ 

⎝ ⎝ 2 ⎠ ⎠ 

where I(t) describes the variation in the intensity of 

contrast uptake as a function of time; a0 is the intensity 

before the arrival of the contrast agent; a1 is linked to 

the maximum value of contrast uptake; a2 is linked to the 

rise time to the peak intensity; p is a coefficient related to 

the increase in intensity; q is a coefficient related to the 

decrease in intensity; A and B are arbitrary parameters. 

The fitted curve was obtained by adjusting all the 

coefficients of the equation (called the IGR equation) 

to obtain a sum of the least-squares differences between 

the linear raw data and the modeled values as close to 0 

as possible. Equation parameters were derived through 

the mathematical model so that asymptotic values were 

properly defined. This fitting was performed using the 

Solver program in Excel ® . Through this modeling step, it 

was possible to avoid recirculation so that the conditions 

required to apply the time intensity method were fulfilled. 

Indeed, the IGR equation was used to perfectly fit the 

wash-in part of the curve while the wash-out part was 


Vmax 

PI 

V0 

Power (a.u.) 

140 

120 

100 

80 

60 

40 

20 

Slope coefficient of the WI 

0 

-20 0 20 40 60 80 100 120 140 

TL Tmax 

t /s 

TPI 

FWHM 

adjusted so that recirculation was not taken into account 

in the final fitted curve (Figure 7). This adjustment is often 

performed [31] to ensure that the conditions required 

for the time intensity method are adequately verified. 

Once the fitted curve was determined, the semi-quantitative 

perfusion parameters were derived according to their 

previously described definitions. 

Statistical analysis 

Intra-operator variability was measured as the coefficient 

of variation (CV) which is the ratio of the SD of a specific 

parameter to its mean. CV = SD/mean. 

For each set of experiments, the CV was evaluated 

and recorded for each of the seven semi-quantitative 

perfusion parameters. An overall range of variation was 

additionally provided in the “Results” part. 



Fitted curve 

Figure 6 The graph displays an example of a time intensity curve with 4 of 

its 7 associated perfusion parameters: the peak intensity or peak intensity 

(difference between Vmax and V0), the time to peak intensity or time to peak 

intensity (the difference between Tmax and TL), the slope coefficient of the 

wash-in (the slope of the tangent of the wash-in at half maximum) and the 

full width at half maximum or FWHM (corresponding to a first approximation 

of the mean transit time). The three other perfusion parameters extracted 

from the time intensity curve were the area under the curve, the area under the 

wash-in and the area under the wash-out. PI: Peak intensity; TPI: Time to peak 

intensity. 

Power (a.u.) 


40 

30 

20 

10 

0 


Fitted curve 

Recirculation 

0 20 40 60 

t/s 

Figure 7 This graph displays both a time intensity curve and its associated 

fitted curve. Recirculation is avoided through the modeling process so 

that the conditions required to apply the time intensity method are fulfilled: the 

Gustave Roussy Institute equation perfectly fits the wash-in part of the curve 

while the wash-out part is adjusted so that recirculation is not taken into account 

in the final fitted curve. 

Table 1 Single straight pipe phantom: intra-operator variability 

of semi-quantitative perfusion parameters following five 

0.02/0.05/0.08 mL bolus injections of SonoVue ® 

0.02 mL/ 

CV (%) 

0.05 mL/ 

CV (%) 

0.08 mL/ 

CV (%) 

RESULTS 

PI TPI Slope of 

the WI 

FWHM AUC AUWI AUWO 

6.03 9.78 9.57 6.43 9.40 9.97 11.11 

9.27 10.14 8.28 13.24 5.23 12.76 6.84 

20.87 10.10 23.52 17.43 5.87 23.72 2.94 

CV: Coefficient of variation; PI: Peak intensity; TPI: Time to peak intensity; 

FWHM: Full width at half maximum; AUC: Area under the curve; AUWI: 

Area under the wash-in; AUWO: Area under the wash-out. 

In vitro experiments 

Three different phantoms were tested. Acquisitions were 

obtained after five injections of SonoVue ® . 

1st phantom - Single straight pipe phantom results: 

Three volumes of SonoVue ® were tested: 0.02, 0.05 and 

0.08 mL. For each volume, five fitted TICs were obtained 

following the five contrast agent injections. Data analysis 

was performed according to the protocol detailed in the 

“Materials and Methods” part: semi-quantitative perfusion 

parameters were extracted directly from the fitted TICs and 

their associated CV values were evaluated. The 0.02, 0.05 

and 0.08 mL five injections respectively led to CV values 

ranging from 6.03% to 11.11%, from 5.23% to 13.24% and 

from 2.94% to 23.72%. Table 1 shows perfusion parameter 

CV values obtained following each set of experiments. 

2nd phantom - Three intertwined pipe phantom results: 

The five fitted TICs resulting from the series of 0.03 and 

0.06 mL bolus injections of SonoVue ® were analyzed using 

the IGR model. Intra-operator variability values were 

found to respectively range from 2.33% to 9.65% and 

from 6.12% to 11.62%. CV values associated with each 

perfusion parameter are shown in Table 2. 

For both these phantoms, maximum CV values were 

found in correspondence with the highest injected dose 

of SonoVue ® . This observation might impact on the linear 

assumption. However, as previously mentioned in the 

“Time Intensity Method” part, to transfer in vitro results 

into clinical context, the concentration of interest is the 

IGR one which remains in the linear range. 

3rd phantom - Dialyzer results: Data analysis was performed 

following five 0.10 mL bolus injections of SonoVue 

® . This series of experiments led to intra-operator 

variability values ranging from 8.11% to 19.11%. Table 3 

provides more detailed results associated with each evaluated 

semi-quantitative perfusion parameter. 

In vivo experiments 

Intra-operator variability studies were performed on five 


Variability (%) 


30 

20 

10 

0 

30 

20 

10 

0 

Table 2 Three intertwined pipe phantom: intra-operator variability 

of semi-quantitative perfusion parameters following 

five 0.03/0.06 mL bolus injections of SonoVue ® 

0.03 mL/ 

CV (%) 

0.06 mL/ 

CV (%) 

PI 

FWMH 


the WI 

mice following three 0.02 mL, 0.05 mL or 0.1 mL bolus 

injections of SonoVue ® . Experiments were performed 

over 5 d. 

Chemical anesthesia: Four mice underwent chemical 

anesthesia. The body weight was found to be 23.5 g (min: 

22.6 g; max: 25 g) throughout the experiments. As experiments 

lasted over 5 d and due to the rapid doubling time 

of melanoma cells [32-34] , tumor volume ranged from 93.8 

to 599.7 mm 3 with a mean tumor value of 339.39 mm 3 . We 

calculated the semi-quantitative perfusion parameters directly 

from the TICs using the IGR mathematical model. 

CV values ranged from 1.48% to 29.97%. Table 4 shows 

variability values associated with each perfusion parameter 

for each mouse. 

Gaseous anesthesia: One mouse underwent gaseous 

anesthesia. It weighed 24.6 g. The tumor volume was 

503.56 mm 3 . CV values were determined based on the 

fitted TICs and ranged from 1.90% to 24.96%. More detailed 

results are provided in Table 4. 



3.16 7.69 9.65 5.56 2.33 8.55 5.32 

7.85 8.60 11.62 7.53 6.73 9.52 6.12 






30 

20 

10 

0 

30 

20 

10 

0 

TPI 

AUC 



30 

20 

10 

0 

Table 3 Dialyzer: intra-operator variability of semi-quantitative 

perfusion parameters following five 0.10 mL bolus injections 

of SonoVue ® 

0.10 mL/ 

CV (%) 

Slope to PI 


the WI 

Single pipe: 0.02 mL SonoVue ® 



Three pipes: 0.03 mL SonoVue ® 

Three pipes: 0.06 mL SonoVue ® 

Dialyser: 0.10 mL SonoVue ® 

Mouse 1: 0.10 mL SonoVue ® 





Figure 8 This graph shows the variability of perfusion parameters involved in both the in vitro and in vivo experiments. Five injections were recorded for 

each of the three phantoms and three for each mouse. The results demonstrated less than 30% overall variability, whatever the perfusion parameter. CV: Coefficient 

of variation; PI: Peak intensity; TPI: Time to peak intensity; FWHM: Full width at half maximum; AUC: Area under the curve; AUWI: Area under the wash-in; AUWO: 

Area under the wash-out. 


30 

20 

10 

0 

AUWI 


9.66 8.11 10.27 19.11 9.31 13.89 13.36 




DISCUSSION 

In this study, intra-operator variability was assessed through 

the determination of the coefficients of variation of semiquantitative 

perfusion parameters using three distinct 

phantoms as well as in vivo. Throughout the experiments, 

CV values were consistently lower than 30% (Figure 8). 

The area under the curve and the area under the wash-out 

exhibited CV values below 15.79% both in vitro and in vivo. 

Sources of variability 

For each set of experiments, conditions such as the probe, 

the phantom, the whole circuit and the settings of the ultrasound 

scanner were maintained unchanged so that the 

assembly remained identical throughout the acquisitions. 

The first source of variation could come from the ultrasound 

contrast agent itself. Indeed, before each injection, SonoVue 

® was reconstituted by manual agitation. Consequently, 

the solution may not have been identically homogeneous 

throughout the experiments. In addition, the precision of 

the syringe used to administer SonoVue ® (within 0.01 mL) 

was low compared to the injected doses. Consequently, 

variations may have occurred even prior to any acquisition. 



30 

20 

10 

0 

AUWO


Table 4 In vivo studies: intra-operator variability of semi-quantitative perfusion parameters following three 0.02/0.05/0.1 mL bolus 

injections of SonoVue ® 

0.02 mL/ 

0.05 mL/ 

0.1 mL/ 

CV (%) 

The second source of variation could come from the 

injection step. Manual injections were performed by the 

same operator and a mark was drawn on the injection 

site so that the same site was used throughout the experiment. 

A new syringe was used for each injection. However, 

even if the mark allowed us to maintain the same 

injection site, it did not provide information concerning 

the exact position of the syringe within the pipe. In addition, 

even though the injection was administered by 

the same operator, variations could have occurred as it 

was performed manually (rate or angle of the injection). 

Other errors may have affected the data analysis part. 

A region of interest had to be selected to compute the 

TICs. It had to be the same for all TICs. However, as a 

new ROI was manually drawn for each injection, results 

may have been tarnished because of mistakes. Additional 

sources of variation can occur in vivo. Indeed, even if 

mice were maintained asleep, their physiological parameters 

were not entirely monitorable and variations may 

have occurred during the experiments. 

The next step concerned TIC fitting. To ensure that 

no variations could come from the solver itself, a series 

of ten fittings were performed on the same TIC. The parameters 

provided by the IGR mathematical model were 

exactly the same for all the curves which allowed us to 

conclude that only the first three steps mentioned above 

may have induced variations in the results. 

Study limitations 

First, in vitro, the fluid used was water at ambient temperature 

which did not exhibit the same ultrasound 

properties as blood [35-37] (Table 5). In addition, none of 

the phantoms contained tissue-mimicking material [38,39] : 

the first two were composed of silicone pipes leading to 

the same remark as with the fluid: the ultrasound properties 

of the silicone are different from those of vessels. 


Mouse PI TPI Slope of the WI FWHM AUC AUWI AUWO 

Chemical anaesthesia 1 18.99 14.04 23.85 28.87 15.79 18.43 15.46 

2 27.60 8.33 25.75 18.90 9.06 28.39 8.12 

3 11.39 4.41 1.48 18.44 10.76 14.73 13.58 

4 27.88 5.68 28.82 29.97 11.21 26.22 12.42 

Gaseous anaesthesia 5 1.90 17.63 10.09 24.96 12.32 12.43 12.79 

CV: Coefficient of variation; PI: Peak intensity; TPI: Time to peak intensity; FWHM: Full width at half maximum; AUC: Area under the curve; AUWI: Area 

under the wash-in; AUWO: Area under the wash-out. 

Table 5 Acoustic properties of different media 

Density 

(kg/m 3 ) 

Velocity 

(m/s) 

Attenuation coefficient 

(dB/cm at 1 MHz) 

Impedance 

(MRayl) 

Blood 1057 1575 0.18 1.61 

Water 1000 1480 0.0022 1 

1.51 (50℃) 

1 Quadratic frequency dependence of this attenuation coefficient. Sources: 

Hedrick et al [36] , Gupta et al [35] , Goldstein et al [37] . 

The properties of the third phantom were more similar 

to those of the microvascularization due to its dimensions. 

However, the parallelism with the capillaries did 

not reflect the complex and irregular structure of tumor 

microvascularization. Consequently, the three increasingly 

complex phantoms we worked with were mainly used for 

intra-operator variability evaluations and their properties 

tend to mimic only some in vivo properties which might 

induce difficulties in transferring in vitro results to in vivo 

ones. Moreover, in vivo, variability measures were based 

on three injections. Having more injections to interpret 

might have provided us with a better statistical analysis: 

this last limitation was offset by the number of mice 

we worked on. Another limitation might concern the 

stability of the ultrasound contrast agent. Indeed, each 

experiment duration was less than 2 h on account of 

the stability of SonoVue ® over time which is 6 h after its 

reconstitution as described by Schneider [11] . However, recent 

studies reported a significant incidence of spontaneous 

gas diffusion phenomena on temporal evolution of 

contrast microbubble size [40-42] . In the following study, gas 

diffusion phenomena occurring for 2 h from initial formation 

of contrast agent was neglected: this assumption 

might impact the results. Finally, as previously mentioned, 

the precision of the syringe was a source of variability 

and the absence of any measurements performed to accurately 

evaluate microbubble concentration at the injection 

time might be a limitation. 

Intra-operator variability studies using MRI, CT, PET and 

US 

Several intra-operator variability studies using MRI, CT 

and PET have been described in the literature. These reported 

an overall intra-observer variability ranging from 

3% to 30% [43-50] . The ranges of the semi-quantitative 

perfusion parameters we evaluated were consistent with 

those reported in the literature. Evelhoch et al [45] analyzed 

CV for the initial area under the gadolinium diethylenetriaminepentaacetate 

uptake vs time curve (IAUC) in 19 patients 

examined with two scans. The CV was found to be 

18%. Wells et al [47] evaluated regional flow and the volume 

of tissue distribution of the contrast agent in tumor and 

normal tissue in 5 patients who underwent two PET-CT 

using inhaled C 15 O2 1 wk apart. They obtained CV values 

ranging from 9% to 14% (11% in the tumor) for the flow 

and from 3% to 13% (6% in the tumor) for the volume 


distribution. Myocardial perfusion values using CT imaging 

were determined by Groves et al [49] using two different 

approaches: the maximum-slope method and the peak 

method. CV values ranging from 12.6% to 23.7% for 

intra-observer agreement were observed. No published 

studies on intra-operator variability using DCE-US were 

found in the literature. Our results are concordant with 

these previous findings since the overall intra-operator 

variability of the semi-quantitative parameters observed 

both in vivo and in vitro ranged from 1.48% to 29.97%. 

Anti-angiogenesis therapies and DCE-US imaging 

Anti-angiogenic treatments inhibit the formation of neoblood 

vessels in tumors obstructing their dissemination 

because of the lack of a blood supply. Such drugs exert 

activity primarily on the microvascularization: they may 

be effective even if no obvious change in tumor shape 

is observed after their administration. In order for functional 

imaging to be efficient in assessing such treatments, 

the variability of any semi-quantitative perfusion parameters 

should be lower than any reduction in perfusion. 

Thomas et al [51] found a decrease of 40% in AUC values, 

using DCE-MRI, at day 28 in 43 patients suffering from 

advanced cancers (24 colorectal, 1 breast, 2 mesothelioma, 

6 neuroendocrine, 2 renal and 8 others) and who received 

single-agent PTK/ZK. Other studies demonstrated that 

reductions in perfusion following anti-angiogenesis treatments, 

using MRI, CT, PET or US, range from 30% to 

greater than 90% [26,52-55] . For example, Lavisse et al [26] studied 

the evolution of the peak intensity (PI), the TPI and 

the FWHM after the administration of AVE8062. They 

found that 6 h after the injection, the PI value represented 

7% of the initial PI, TPI was three-fold higher than the initial 

TPI and FHWM was twice the initial FWHM. 

In the light of these data, the CV values found in 

the current DCE-US study justified its use as an imaging 

method for assessing anti-angiogenic treatments. 

In addition, in this study, the AUC and AUWO exhibited 

both in vitro and in vivo CV values below 15.79%. 

This is a major result considering the previous findings 

reported by Lassau et al [22,56,57] in different types of tumors 

such as GIST or RCC: among the seven semi-quantitative 

perfusion parameters evaluated, the two parameters which 

always correlated with the RECIST response and overall 

survival were the AUC and the AUWO. These two complementary 

observations highlight the reliability of such 

parameters in assessing anti-angiogenic treatments: AUC 

and AUWO are associated to a good correlation to RE- 

CIST response as well as to low intra-operator variability 

values. The TPI may also be considered a parameter of interest 

as it exhibited CV values in a range noticeably similar 

to AUC and AUWO: it ranged from 4.41% to 17.63%. 

Dynamic T1-weighted MRI and CT are commonly 

used in assessing tumor angiogenesis as DCE-US suffers 

from some limitations. One of its major drawbacks 

is its operator dependence. In addition, CV values might 

depend on the organ as some can be more challenging 

to image such as the liver suffering from respiration artifacts. 

There is also a limited depth penetration making 

imaging of deepest regions difficult [50,58] . Finally, some 



anti-angiogenic treatments mainly involve change in tumor 

vasculature permeability without tumor flow. Consequently, 

as ultrasound contrast agents are purely intravascular, 

DCE-US can only provide tumor blood flow 

information: no information concerning tumor permeability 

can be determined [50] . 

On the other hand, further studies involving intraoperator 

variability might support DCE-US as the imaging 

method of choice for the early evaluation of antiangiogenic 

drugs because it also has many additional 

specific advantages. Contrast agents used in DCE-MRI 

are extracellular ones and no linear relationship exists, 

whatever the dose between the measured signal and the 

concentration of the MRI contrast agents [50] . DCE-US 

involves working with purely intravascular contrast agents. 

In addition, within a certain range, the measured intensity 

exhibits a linear relationship with microbubble concentration 

making it possible to assess perfusion parameters. In 

spite of the advantage of a linear relationship between 

the change in CT intensity and the concentration of the 

contrast agent as well as a high spatial resolution, DCE- 

CT has a low sensitivity and high concentrations of contrast 

agent can be toxic [50] . PET and SPECT modalities 

are highly sensitive to very low tracer concentrations but 

exhibit a poor resolution [50] compared to that of DCE-US. 

In addition DCE-US has advantages linked to ultrasound 

imaging: it is non-invasive, easy to use, not expensive, 

rapid and widely available. 

Further studies 

In this study, intra-operator variability measurements 

were based on semi-quantitative parameters, i.e. parameters 

extracted from the measured TIC within phantoms 

or tumors. Such parameters are often determined to 

estimate physiological parameters but do not take into account 

variations linked to physiological effects [31] . Blood 

flow and blood volume could be determined using methods 

that take into account patient hemodynamic conditions 

as well as the way the contrast agent is injected [31] 

which are elements included in the arterial input function. 

Consequently, further studies including the arterial input 

function will have to be performed to determine its influence 

on the DCE-US technique. 

This work performed using in vitro and in vivo models 

demonstrated that among the seven semi-quantitative 

perfusion parameters, two (the AUC and the AUWO) 

linked to the blood volume and blood flow [9,10] exhibited 

an intra-operator variability value below 15.79% and 

could be the most reliable for early evaluation of antiangiogenic 

treatments. 


The authors thank Lorna Saint Ange for editing. 

COMMENTS 

Background 

Early functional imaging of anti-angiogenesis treatments in oncology is of major 

importance. Dynamic contrast-enhanced ultrasonography (DCE-US) is now 



commonly recognized as a functional imaging technique able to evaluate such 

therapies as it is a sensitive and highly available modality allowing early prediction 

of tumor response to treatments based on changes in vascularity before 

any morphological ones occur. 

Research frontiers 

Microbubble contrast agents for DCE-US have developed during the past 10 years 

and are currently approved in Europe, Asia and Canada. Nowadays, ultrasound 

provides an ideal imaging modality for angiogenesis: it is widely available, not 

ionizing, low cost and provides real time imaging. However, until now, information 

on intra-operator variability in perfusion parameter measurements performed 

using DCE-US is lacking. In this study, the authors evaluated such variability and 

highlighted values similar to previous findings using other imaging modalities. 

Innovations and breakthroughs 

DCE-US is supported by the French National Cancer Institute which is currently 

studying the technique in several pathologies to establish the optimal perfusion 

parameters and timing for quantitative anticancer efficacy assessments: currently 

400 patients with 1096 DCE-US demonstrated that the area under the 

curve quantified at 1 mo could be a robust parameter to predict response at 

6 mo. The following study is the first one analyzing intra-operator variability in 

perfusion parameter measurements performed using DCE-US. Our study would 

suggest that DCE-US technique has comparable intra-operator variability than 

other functional imaging modalities that are currently used in routine. 

Applications 

By evaluating intra-operator variability in perfusion parameter measurements 

performed using DCE-US, this study may confirm the interest of dynamic 

contrast enhanced-ultrasonography as functional imaging in anti-angiogenic 

therapy evaluations. 

Terminology 

DCE-US involves the use of microbubble contrast agents and specialized imaging 

techniques to evaluate blood flow and tissue perfusion. Intra-operator variability 

studies aim to determine the variation in measurements performed by a 

single operator and instrument on the same item and under the same conditions. 

Peer review 

This is an interesting study and may draw the readers’ attention because the 

authors evaluated the feasibility and reproducibility of DCE-US through in vitro 

and in vivo. Moreover, I think that this study would guide the readers about the 

methods of basic research in the areas of radiology. Unfortunately, strength of 

reported findings is limited by some experimental constraints and manuscript 

presentation needs several improvements before publication. 

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43 Ng CS, Raunig DL, Jackson EF, Ashton EA, Kelcz F, Kim 

KB, Kurzrock R, McShane TM. Reproducibility of perfusion 

parameters in dynamic contrast-enhanced MRI of lung and 

liver tumors: effect on estimates of patient sample size in 

clinical trials and on individual patient responses. AJR Am J 

Roentgenol 2010; 194: W134-W140 

44 Marcus CD, Ladam-Marcus V, Cucu C, Bouché O, Lucas L, 



Hoeffel C. Imaging techniques to evaluate the response to 

treatment in oncology: current standards and perspectives. 

Crit Rev Oncol Hematol 2009; 72: 217-238 

45 Evelhoch JL, LoRusso PM, He Z, DelProposto Z, Polin L, 

Corbett TH, Langmuir P, Wheeler C, Stone A, Leadbetter J, 

Ryan AJ, Blakey DC, Waterton JC. Magnetic resonance imaging 

measurements of the response of murine and human tumors 

to the vascular-targeting agent ZD6126. Clin Cancer Res 

2004; 10: 3650-3657 

46 Morgan B, Utting JF, Higginson A, Thomas AL, Steward WP, 

Horsfield MA. A simple, reproducible method for monitoring 

the treatment of tumours using dynamic contrast-enhanced 

MR imaging. Br J Cancer 2006; 94: 1420-1427 

47 Wells P, Jones T, Price P. Assessment of inter- and intrapatient 

variability in C15O2 positron emission tomography 

measurements of blood flow in patients with intra-abdominal 

cancers. Clin Cancer Res 2003; 9: 6350-6356 

48 Cenic A, Nabavi DG, Craen RA, Gelb AW, Lee TY. Dynamic 

CT measurement of cerebral blood flow: a validation study. 

AJNR Am J Neuroradiol 1999; 20: 63-73 

49 Groves AM, Goh V, Rajasekharan S, Kayani I, Endozo R, 

Dickson JC, Menezes LJ, Shastry M, Habib SB, Ell PJ, Hutton 

BF. CT coronary angiography: quantitative assessment of 

myocardial perfusion using test bolus data-initial experience. 

Eur Radiol 2008; 18: 2155-2163 

50 Miller JC, Pien HH, Sahani D, Sorensen AG, Thrall JH. Imaging 

angiogenesis: applications and potential for drug development. 

J Natl Cancer Inst 2005; 97: 172-187 

51 Thomas AL, Morgan B, Horsfield MA, Higginson A, Kay A, 

Lee L, Masson E, Puccio-Pick M, Laurent D, Steward WP. 

Phase I study of the safety, tolerability, pharmacokinetics, 

and pharmacodynamics of PTK787/ZK 222584 administered 

twice daily in patients with advanced cancer. J Clin Oncol 

2005; 23: 4162-4171 

52 Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, 

Tong RT, Chung DC, Sahani DV, Kalva SP, Kozin SV, Mino 

M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark 

JW, Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito 

PC, Lauwers GY, Jain RK. Direct evidence that the VEGFspecific 

antibody bevacizumab has antivascular effects in human 

rectal cancer. Nat Med 2004; 10: 145-147 

53 Meijerink MR, van Cruijsen H, Hoekman K, Kater M, van 

Schaik C, van Waesberghe JH, Giaccone G, Manoliu RA. The 

use of perfusion CT for the evaluation of therapy combining 

AZD2171 with gefitinib in cancer patients. Eur Radiol 2007; 

17: 1700-1713 

54 Lassau N, Lamuraglia M, Vanel D, Le Cesne A, Chami L, 

Jaziri S, Terrier P, Roche A, Leclere J, Bonvalot S. Doppler US 

with perfusion software and contrast medium injection in the 

early evaluation of isolated limb perfusion of limb sarcomas: 

prospective study of 49 cases. Ann Oncol 2005; 16: 1054-1060 

55 Miles KA, Griffiths MR. Perfusion CT: a worthwhile enhancement? 

Br J Radiol 2003; 76: 220-231 

56 Lassau N, Chebil M, Koscielny S, Chami L, Bendjilali R, Roche 

A. Dynamic Contrast-enhanced Ultrasonography (DCE-US) 

with Quantification for the Early Evaluation of HCC Treated 

by Bevacizumab: Which Parameters? Radiological Society of 

North America. 95th Scientific Assembly and Annual Meeting; 

2009 Nov 29-Dec 4; Chicago: Mc Cormick Place 

57 Lassau N, Chebil M, Chami L, Bidault S, Girard E, Roche A. 

Dynamic contrast-enhanced ultrasonography (DCE-US): a 

new tool for the early evaluation of antiangiogenic treatment. 

Target Oncol 2010; 5: 53-58 

58 Quaia E, D'Onofrio M, Palumbo A, Rossi S, Bruni S, Cova 

M. Comparison of contrast-enhanced ultrasonography versus 

baseline ultrasound and contrast-enhanced computed 

tomography in metastatic disease of the liver: diagnostic performance 

and confidence. Eur Radiol 2006; 16: 1599-1609 

S- Editor Cheng JX L- Editor O’Neill M E- Editor Zheng XM 


W J R 



doi:10.4329/wjr.v3.i3.82 

Paraparesis induced by extramedullary haematopoiesis 

Paolo Savini, Arianna Lanzi, Giorgio Marano, Chiara Carli Moretti, Giovanni Poletti, Giuseppe Musardo, 

Francesco Giuseppe Foschi, Giuseppe Francesco Stefanini 

Paolo Savini, Arianna Lanzi, Giorgio Marano, Giuseppe 

Musardo, Francesco Giuseppe Foschi, Giuseppe Francesco 

Stefanini, Department of Internal Medicine, Faenza Hospital, 

viale Stradone 9, 48018 Faenza, Italy 

Chiara Carli Moretti, Department of Radiology, Faenza Hospital, 

viale Stradone 9, 48018 Faenza, Italy 

Giovanni Poletti, Department of Pathology, Ravenna Hospital, 

viale Randi 5, 48121 Ravenna, Italy 

Author contributions: Savini P refer to physician of the clinical 

case; Lanzi A and Marano G contributes to writing the manuscript; 

Carli Moretti C provided radiologic images of the case; 

Poletti performed laboratory analysis; Musardo G and Foschi FG 

screened the literature and contributed to writing the first draft of 

the paper; Stefanini GF was responsible for the final approval of 

the manuscript. 

Correspondence to: Paolo Savini, MD, Department of Internal 

Medicine, Faenza Hospital, viale Stradone 9, 48018 Faenza, 

Italy. p.savini@ausl.ra.it 

Telephone: +39-546-601111 Fax: +39-546-601517 

Received: November 13, 2010 Revised: January 10, 2011 

Accepted: January 17, 2011 


Abstract 

We describe a case of worsening paraparesis induced 

by spinal cord compression at T6-T7 levels associated 

with compensatory extramedullary haematopoiesis from 

a compound heterozygote for haemoglobin E and for 

β-thalassemia. An emergency T3-T9 laminectomy was 

performed with excision of the masses and complete 

rehabilitation of the patient. 


Key words: Extramedullary hematopoiesis; Thalassemia; 

Anemia; Spinal cord compression; Laminectomy 

Peer reviewers: Yi-Xiang Wang, MMed, PhD, Associate Professor, 

Department of Diagnostic Radiology and Organ Imaging, 

Prince of Wales Hospital, The Chinese University of Hong Kong, 

Shatin, NT, Hong Kong, China; Kennith F Layton, MD, FAHA, 

Division of Neuroradiology and Director of Interventional Neu- 



Radiology 

roradiology, Department of Radiology, Baylor University Medical 

Center, 3500 Gaston Avenue, Dallas, TX 75246, United States 

Savini P, Lanzi A, Marano G, Moretti CC, Poletti G, Musardo G, 

Foschi FG, Stefanini GF. Paraparesis induced by extramedullary 

haematopoiesis. World J Radiol 2011; 3(3): 82-84 Available 

from: URL: http://www.wjgnet.com/1949-8470/full/v3/i3/ 

82.htm DOI: http://dx.doi.org/10.4329/wjr.v3.i3.82 

INTRODUCTION 

Extramedullary haematopoiesis (EMH) is a physiologic response 

to chronic anemia, observed in various hematologic 

disorders such as thalassemias [1] , myelofibrosis and polycythemia. 

Since the first description by Gatto et al [2] , several 

cases of EMH at different sites have been reported. 

The EMH, as a tumor-like mass, is commonly seen 

in the liver, spleen and lymph nodes. Involvement of the 

epidural space causing spinal cord compression has rarely 

been reported [3] . 

Because of its rarity, there are no evidence-based guidelines 

for the treatment of paraspinal pseudotumors caused 

by EMH. Management options include hypertransfusion, 

radiotherapy, surgery or a combination of these modalities. 

Recently, hydroxyurea or erythropoietin in combination 

with radiotherapy as treatment was described [4-6] , but 

management still remains controversial. 

Decompressive laminectomy, as in our case, has been 

used in patients with rapid neurological deterioration [7] . 

We hereby present a case of EMH in a 21-year-old man 

with thalassemia presenting with paraplegia due to a spinal 

cord compression that was treated successfully with surgery. 

CASE REPORT 




CASE REPORT 

A 21-year-old man with a not well defined history of 

transfusion-dependent microcytic anemia in his native 

country, Bangladesh, presented to the emergency department 

with worsening paraparesis. 


Figure 1 Pre-operative computed tomography scan of the chest without contrast 

media showing the large bilateral costal masses (white arrows) and an 

intracanalicular extradural mass (black arrow). 

Figure 2 Pre-operative “bone window” computed tomography scan of the 

chest without contrast media shows large bilateral, well circumscribed 

lobulated soft tissue masses that cause widening of the ribs (short arrows) 

and periosteal reaction, without interruption of cortical bone (thin long 

arrow). Coexisting involvement of the sternum body (thick long arrow). 

Figure 3 Pre-operative “bone window” computed tomography scan without 

contrast media: the vertebral body is devoid of bony erosion and has a 

lacey appearance. 

Computed tomography (Figures 1-3) and magnetic resonance 

imaging (MRI, Figures 4-6) revealed bilateral paravertebral 

soft-tissue masses at T4-L1 levels and a mass with 

the same features was seen inside the vertebral canal inducing 

spinal cord compression at T4-T9 levels. Furthermore, 

a marked medullary expansion of the bony structures was 


Savini P et al . Extramedullary haematopoiesis with paraparesis 

Figure 4 Preoperative axial magnetic resonance imaging, T2 weighted, 

shows paravertebral and intracanal masses, isointense with the spinal 

cord, widening the ribs (short arrows) and causing cord compression (long 

arrow). 

Figure 5 Preoperative sagittal MRI, T2 weighted, shows masses extending 

from T4 to T9 with cord compression (white arrows), embedded within the epidural 

fat and isointense with the spinal cord. 

A 

Figure 6 Preoperative sagittal magnetic resonance imaging, T1 weighted, 

without contrast media (A) (long arrows), and after Gadolinium administration 

(B) (short arrows) shows poor and homogeneous contrast enhancement 

of the masses. 

present. Laboratory analyses showed a haemoglobin (Hb) 

level of 8.5 g/dL and mean corpuscular volume (MCV) of 

68 fL. Hb electrophoresis revealed HbE at 45%, HbF at 

30% and HbA2 at 20%. 

Molecular analysis showed the patient was a compound 

heterozygote for HbE (β-26 glutamine → lysine) 


B

Savini P et al . Extramedullary haematopoiesis with paraparesis 

and for β-thalassemia (β+IVS1-nt5). All these findings 

appeared to be associated with compensatory extramedullary 

haematopoiesis. 

An emergency T3-T9 laminectomy was performed 

with a complete excision of the masses. A morphological 

and immunohistochemical analysis was then carried out. 

The masses were composed of a heterogeneous cellular 

population resembling physiological haematopoiesis in all 

its components. 

The patient received a rehabilitation cycle and five 

months after the surgery, with continuing red blood cell 

transfusions, remains free of symptoms. 

DISCUSSION 

HbE (β26Glu → Lys) is the most common Hb variant in 

Southeast Asia and the second most prevalent worldwide. 

HbE, when associated with β thalassemia (HbE/β-thalassemia) 

in a compound heterozygous state, results in a 

clinically severe condition. HbE activates a cryptic splice 

site that produces non-functional mRNAs. Hb IVS1-1 is 

a Mediterranean mutation that affects mRNA processing 

giving rise to β (o)-thalassemia. HbE/β thalassemia has a 

very variable clinical phenotype. HbE/β-thalassemia generally 

manifests with severe anemia where individuals exhibit 

β-thalassemia major with regular blood transfusions 

or β-thalassemia intermedia with periodic blood transfusions. 

Extramedullary haematopoiesis is a consequence of 

insufficient bone marrow function that is unable to meet 

circulatory demands. Thalassemia major or intermedia, 

congenital spherocytosis, congenital haemolytic anemia 

and sickle cell anemia account for most cases of EMH. It 

is rarely seen in myelofibrosis and Gaucher’s disease. 

Intrathoracic EMH is most often visualized on the 

chest roentgenogram or the chest computed tomography 

(CT) scan as single or multiple paravertebral mass lesions. 

While a paravertebral mass may represent EMH, other 

disorders of the posterior mediastinum, such as neurogenic 

tumor, lymphoma, primary and metastatic malignancy, 

paravertebral abscess, lateral meningocele, and 

extrapleural cyst, must be considered. 

The characteristic features observed in the chest roentgenogram 

and the chest CT scan were helpful in recogniz- 


ing intrathoracic EMH. These included the following 8] : (1) 

Widening of the ribs by expansion of the medullary cavity 

or by periosteal elevation, without bony erosion; (2) The 

presence of a unilateral or bilateral well-circumscribed lobulated, 

paravertebral mass lesion usually located caudal to 

the sixth thoracic vertebrae; and (3) The absence of calcification 

and the presence of adipose tissue within the mass. 

MRI is currently the technique of choice in evaluating 

spinal EMH. On MRI, EMH is usually characterized by 

lobular masses with increased signal intensity compared to 

that of the red marrow in the adjacent vertebral bodies [7] . 

The lack of gadolinium enhancement allows its differentiation 

from other epidural masses such as abscesses or 

metastases. 

REFERENCES 

1 Cappellini MD, Musallam KM, Taher AT. Insight onto the 

pathophysiology and clinical complications of thalassemia 

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2 Gatto I, Terrana V, Biondi L. [Compression of the spinal cord 

due to proliferation of bone marrow in epidural space in a 

splenectomized person with Cooley's disease]. Haematologica 

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3 Logothetis J, Constantoulakis M, Economidou J, Stefanis C, 

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aspects. Neurology 1972; 22: 294-304 

4 Cario H, Wegener M, Debatin KM, Kohne E. Treatment with 

hydroxyurea in thalassemia intermedia with paravertebral 

pseudotumors of extramedullary hematopoiesis. Ann Hematol 

2002; 81: 478-482 

5 Cianciulli P, Sorrentino F, Morino L, Massa A, Sergiacomi 

GL, Donato V, Amadori S. Radiotherapy combined with 

erythropoietin for the treatment of extramedullary hematopoiesis 

in an alloimmunized patient with thalassemia intermedia. 

Ann Hematol 1996; 72: 379-381 

6 Malik M, Pillai LS, Gogia N, Puri T, Mahapatra M, Sharma 

DN, Kumar R. Paraplegia due to extramedullary hematopoiesis 

in thalassemia treated successfully with radiation 

therapy. Haematologica 2007; 92: e28-e30 

7 Dibbern DA Jr, Loevner LA, Lieberman AP, Salhany KE, 

Freese A, Marcotte PJ. MR of thoracic cord compression 

caused by epidural extramedullary hematopoiesis in myelodysplastic 

syndrome. AJNR Am J Neuroradiol 1997; 18: 363-366 

8 Alam R, Padmanabhan K, Rao H. Paravertebral mass in a 

patient with thalassemia intermedia. Chest 1997; 112: 265-267 

S- Editor Cheng JX L- Editor Lutze M E- Editor Zheng XM 


W J R 





Acknowledgments to reviewers of World Journal of 

Radiology 

Many reviewers have contributed their expertise and time 

to the peer review, a critical process to ensure the quality 

of World Journal of Radiology. The editors and authors of 

the articles submitted to the journal are grateful to the 

following reviewers for evaluating the articles (including 

those published in this issue and those rejected for this 

issue) during the last editing time period. 

Charles Bellows, MD, Associate Professor, Chief of General 

Surgery, Tulane University, Department of Surgery SL-22, 1430 

Tulane Ave, New Orleans, LA 70112, United States 

Filippo Cademartiri, MD, PhD, Departmento of Radiology - 

c/o Piastra Tecnica - Piano 0, Azienda Ospedaliero-Universitaria di 

Parma, Via Gramsci, 14 - 43100 Parma, Italy 

Sergio Casciaro, PhD, Institute of Clinical Physiology - National 

Research Council,Campus Universitario Ecotekne, Via Monteroni, 

73100 Lecce, Italy 

Chan Kyo Kim, MD, Assistant Professor, Department of Radiology, 

Samsung Medical Center, Sungkyunkwan University School of 

Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, South Korea 



Radiology 

World J Radiol 2011 March 28; 3(3): I 



Stefania Romano, MD, A. Cardarelli Hospital, Department of 

Diagnostic Imaging, Section of General and Emergency Radiology, 

Viale Cardarelli, 9, 80131 Naples, Italy 

Francesco Lassandro, MD, Department of Radiology, Monaldi 

Hospital, via Leonardo Bianchi, Napoli, 80129, Italy 

Kennith F Layton, MD, FAHA, Division of Neuroradiology 

and Director of Interventional Neuroradiology, Department of 

Radiology, Baylor University Medical Center, 3500 Gaston Avenue, 

Dallas, TX 75246, United States 

Yicheng Ni, MD, PhD, Professor, Biomedical Imaging, Interventional 

Therapy and Contrast Media Research, Department 

of Radiology, University Hospitals, K.U. Leuven, Herestraat 49, 

B-3000, Leuven, Belgium 

Yi-Xiang Wang, MMed, PhD, Associate Professor, Department 

of Diagnostic Radiology and Organ Imaging, Prince of 

Wales Hospital, The Chinese University of Hong Kong, Shatin, 

NT, Hong Kong, China 

Ying Xiao, PhD, Professor, Director, Medical Physics, Department 

of Radiation Oncology, Thomas Jefferson University Hospital, 

Philadelphia, PA 19107-5097, United States 

I March 28, 2011|Volume 3|Issue 3|

W J R 




Meetings 

Events Calendar 2011 

January 23-27 

Radiology at Snowbird 

San Diego, Mexico 

January 24-28 

Neuro/ENT at the Beach 

Palm Beach, FL, United States 

February 28-29 

MIAD 2011 - 2nd International 

Workshop on Medical Image 

Analysis and Description for 

Diagnosis System 

Rome, Italy 

February 5-6 

Washington Neuroradiology Review 

Arlington, VA, United States 


MI11 - SPIE Medical Imaging 2011 

Lake Buena Vista, FL, United States 


2nd National Conference Diagnostic 

and Interventional Radiology 2011 

London, United Kingdom 

Februrary 17-18 

VII National Neuroradiology Course 

Lleida, Spain 

February 18 

Radiology in child protection 

Nottingham, United Kingdom 

Februrary 19-22 

COMPREHENSIVE REVIEW OF 

MUSCULOSKELETAL MRI 

Lake Buena Vista, FL, United States 

March 2-5 

2011 Abdominal Radiology Course 

Carlsbad, CA, United States 

March 3-7 

European Congress of Radiology 

Meeting ECR 2011 

Vienna, Austria 

March 6-9 

World Congress Thoracic Imaging - IV 

Bonita Springs, FL, United States 


March 14-18 

9th Annual NYU Radiology Alpine 

Imaging Symposium at Beaver 

Creek 

Beaver Creek, CO, United States 

March 20-25 

Abdominal Radiology Course 2011 

Carlsbad, CA, United States 

March 26-31 

2011 SIR Annual Meeting 

Chicago, IL, United States 

March 28-April 1 

University of Utah Neuroradiology 

2nd Intensive Interactive Brain & 

Spine Imaging Conference 

Salt Lake City, UT, United States 

April 3-8 

1st Annual Ottawa Radiology 

Resident Review 

Ottawa, Canada 

April 3-8 

43rd International Diagnostic Course 

Davos on Diagnostic Imaging and 

Interventional Techniques 

Davos, Switzerland 

April 6-9 

Image-Based Neurodiagnosis: 

Intensive Clinical and Radiologic 

Review, CAQ Preparation 

Cincinnati, OH, United States 

April 28-May 1 

74th Annual Scientific Meeting 

of the Canadian Association of 

Radiologists CAR 

Montreal, Canada 

May 5-8 

EMBL Conference-Sixth 

International Congress on Electron 

Tomography 

Heidelberg, Germany 

May 10-13 

27th Iranian Congress of Radiology 

Tehran, Iran 

May 14-21 

Radiology in Marrakech 

Marrakech, Morocco 


Radiology 

May 21-24 

European Society of Gastrointestinal 

and Abdominal Radiology 2011 

Annual Meeting 

Venice, Italy 

May 23-25 

Sports Medicine Imaging State of 

the Art: A Collaborative Course for 

Radiologists and Sports Medicine 

Specialists 

New York, NY, United States 

May 24-26 

Russian Congress of Radiology 

Moscow, Russia 

May 28-31 

International Congress of Pediatric 

Radiology (IPR) 

London, United Kingdom 

June 4-8 

58th Annual Meeting of the Society 

of Nuclear Medicine 

San Antonio, TX, United States 

June 6-8 

UKRC 2011 - UK Radiological 

Congress 

Manchester, United Kingdom 

June 8-11 

CIRA 2011 - Canadian Internventinal 

Radiology Association Meeting 

Montreal, QC, Canada 

June 9-10 

8th ESGAR Liver Imaging Workshop 

Dublin, Ireland 

June 17-19 

ASCI 2011 - 5th Congress of Asian 

Society of Cardiovascular Imaging 


June 22-25 

CARS 2011 - Computer Assisted 

Radiology and Surgery - 25th 

International Congress and 

Exhibition 

Berlin, Germany 

June 27-July 1 

NYU Summer Radiology 

Symposium at The Sagamore 

Lake George, NY, United States 

July 18-22 

Clinical Case-Based Radiology 

Update in Iceland 

Reykjavik, Iceland 

August 1-5 

NYU Clinical Imaging Symposium 

in Santa Fe 

Santa Fe, NM, United States 

World J Radiol 2011 March 28; 3(3): I 



September 22-25 

European Society of Neuroradiology 

(ESNR) XXXV Congress and 19th 

Advanced Course 

Antwerp, Belgium 

October 12-14 

International Conference Vipimage 

2011 - Computational Vision and 

Medical Image Processing 

Algarve, Portugal 

October 15-16 

Essentials of Emergency and Trauma 

Radiology 


October 23-29 

2011 IEEE NSS - 2011 IEEE Nuclear 

Science Symposium and Medical 

Imaging Conference 

Valencia, Spain 

October 25-28 

NYU Radiology in Scottsdale - Fall 

Radiology Symposium in Scottsdale 

Scottsdale, AZ, United States 

October 28-30 

Fourth National Congress of 

Professionals of Radiological 

Techniques 

Florianópolis, Brazil 

October 28-30 

Multi-Modality Gynecological & 

Obstetric Imaging 


November 3-4 

9th ESGAR Liver Imaging Workshop 

Taormina, Italy 

November 15-19 

EANM 2011 - Annual Congress of 

the European Association of Nuclear 

Medicine 

Birmingham, United Kingdom 


NSS/MIC - Nuclear Science 

Symposium and Medical Imaging 

Conference 2011 

Valencia, Spain 


8th Asia Oceaninan Congress of 

Neuro-Radiology 

Bangkok, Thailand 


W J R 




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standard errors. Give the number of observations and subjects (n). 

Losses in observations, such as drop-outs from the study should be 

reported; (4) Values such as ED50, LD50, IC50 should have their 

95% confidence limits calculated and compared by weighted probit 

analysis (Bliss and Finney); and (5) The word ‘significantly’ should 

be replaced by its synonyms (if it indicates extent) or the P value (if 

it indicates statistical significance). 

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In the interests of transparency and to help reviewers assess any potential 

bias, WJR requires authors of all papers to declare any competing 

commercial, personal, political, intellectual, or religious interests 

in relation to the submitted work. Referees are also asked to indicate 

any potential conflict they might have reviewing a particular 

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Requirements for Manuscripts Submitted to Biomedical Journals: 

Ethical Considerations in the Conduct and Reporting of Research: 

Conflicts of Interest” from International Committee of Medical 

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org/ethical_4conflicts.html. 

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[Name of individual] owns stocks and shares in [name of 

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Statement of informed consent 

Manuscripts should contain a statement to the effect that all human 

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or it should be stated clearly in the text that all persons gave their 

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might disclose the identity of the subjects under study should be 

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of the World Medical Association (Declaration of Helsinki, 1964, 

as revised in 2004). 

Statement of human and animal rights 

When reporting the results from experiments, authors should follow 

the highest standards and the trial should conform to Good Clinical 

Practice (for example, US Food and Drug Administration Good 

Clinical Practice in FDA-Regulated Clinical Trials; UK Medicines 

Research Council Guidelines for Good Clinical Practice in Clinical 

Trials) and/or the World Medical Association Declaration of Helsinki. 

Generally, we suggest authors follow the lead investigator’s national 

standard. If doubt exists whether the research was conducted 

in accordance with the above standards, the authors must explain the 

rationale for their approach and demonstrate that the institutional 

review body explicitly approved the doubtful aspects of the study. 

Before submitting, authors should make their study approved by 

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If human participants were involved, manuscripts must be accompanied 

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the materials and methods (experimental procedures) section must 

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SUBMISSION OF MANUSCRIPTS 

Manuscripts should be typed in 1.5 line spacing and 12 pt. Book 


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start each of the following sections on a new page: Title Page, Abstract, 

Introduction, Materials and Methods, Results, Discussion, 

Acknowledgements, References, Tables, Figures, and Figure Legends. 

Neither the editors nor the publisher are responsible for the 

opinions expressed by contributors. Manuscripts formally accepted 

for publication become the permanent property of Baishideng 

Publishing Group Co., Limited, and may not be reproduced by any 

means, in whole or in part, without the written permission of both 

the authors and the publisher. We reserve the right to copy-edit and 

put onto our website accepted manuscripts. Authors should follow 

the relevant guidelines for the care and use of laboratory animals 

of their institution or national animal welfare committee. For the 

sake of transparency in regard to the performance and reporting of 

clinical trials, we endorse the policy of the ICMJE to refuse to publish 

papers on clinical trial results if the trial was not recorded in a 

publicly-accessible registry at its outset. The only register now available, 

to our knowledge, is http://www.clinicaltrials.gov sponsored 

by the United States National Library of Medicine and we encourage 

all potential contributors to register with it. However, in the case 

that other registers become available you will be duly notified. A 

letter of recommendation from each author’s organization should 

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secrecy of research is protected. 

Authors should retain one copy of the text, tables, photographs 

and illustrations because rejected manuscripts will not be returned 

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damage to photographs and illustrations sustained during mailing. 

Online submissions 

Manuscripts should be submitted through the Online Submission 

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highly recommended to consult the ONLINE INSTRUCTIONS 

TO AUTHORS (http://www.wjgnet.com/1949-8470/g_info_ 

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System may send an email describing the problem to wjr@ 

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manuscript online, do not make a postal contribution. Repeated 

online submission for the same manuscript is strictly prohibited. 

MANUSCRIPT PREPARATION 

All contributions should be written in English. All articles must be 

submitted using word-processing software. All submissions must be 

typed in 1.5 line spacing and 12 pt. Book Antiqua with ample margins. 

Style should conform to our house format. Required information 

for each of the manuscript sections is as follows: 

Title page 

Title: Title should be less than 12 words. 

Running title: A short running title of less than 6 words should be 

provided. 

Authorship: Authorship credit should be in accordance with the 

standard proposed by International Committee of Medical Journal 

Editors, based on (1) substantial contributions to conception and 

design, acquisition of data, or analysis and interpretation of data; (2) 

drafting the article or revising it critically for important intellectual 

content; and (3) final approval of the version to be published. Authors 

should meet conditions 1, 2, and 3. 

Institution: Author names should be given first, then the complete 

name of institution, city, province and postcode. For example, Xu- 

Chen Zhang, Li-Xin Mei, Department of Pathology, Chengde 

Medical College, Chengde 067000, Hebei Province, China. One author 

may be represented from two institutions, for example, George 

Sgourakis, Department of General, Visceral, and Transplantation 

Surgery, Essen 45122, Germany; George Sgourakis, 2nd Surgical 

II March 28, 2011|Volume 3|Issue 3|

Department, Korgialenio-Benakio Red Cross Hospital, Athens 

15451, Greece 

Author contributions: The format of this section should be: 

Author contributions: Wang CL and Liang L contributed equally 

to this work; Wang CL, Liang L, Fu JF, Zou CC, Hong F and Wu 

XM designed the research; Wang CL, Zou CC, Hong F and Wu 

XM performed the research; Xue JZ and Lu JR contributed new 

reagents/analytic tools; Wang CL, Liang L and Fu JF analyzed the 

data; and Wang CL, Liang L and Fu JF wrote the paper. 

Supportive foundations: The complete name and number of supportive 

foundations should be provided, e.g., Supported by National 

Natural Science Foundation of China, No. 30224801 

Correspondence to: Only one corresponding address should be 

provided. Author names should be given first, then author title, affiliation, 

the complete name of institution, city, postcode, province, 

country, and email. All the letters in the email should be in lower 

case. A space interval should be inserted between country name and 

email address. For example, Montgomery Bissell, MD, Professor of 

Medicine, Chief, Liver Center, Gastroenterology Division, University 

of California, Box 0538, San Francisco, CA 94143, United States. 

montgomery.bissell@ucsf.edu 

Telephone and fax: Telephone and fax should consist of +, country 

number, district number and telephone or fax number, e.g., Telephone: 

+86-10-85381892 Fax: +86-10-85381893 

Peer reviewers: All articles received are subject to peer review. 

Normally, three experts are invited for each article. Decision for 

acceptance is made only when at least two experts recommend 

an article for publication. Reviewers for accepted manuscripts are 

acknowledged in each manuscript, and reviewers of articles which 

were not accepted will be acknowledged at the end of each issue. 

To ensure the quality of the articles published in WJR, reviewers of 

accepted manuscripts will be announced by publishing the name, 

title/position and institution of the reviewer in the footnote accompanying 

the printed article. For example, reviewers: Professor 

Jing-Yuan Fang, Shanghai Institute of Digestive Disease, Shanghai, 

Affiliated Renji Hospital, Medical Faculty, Shanghai Jiaotong University, 

Shanghai, China; Professor Xin-Wei Han, Department of 

Radiology, The First Affiliated Hospital, Zhengzhou University, 

Zhengzhou, Henan Province, China; and Professor Anren Kuang, 

Department of Nuclear Medicine, Huaxi Hospital, Sichuan University, 

Chengdu, Sichuan Province, China. 

Abstract 

There are unstructured abstracts (no more than 256 words) and 

structured abstracts (no more than 480). The specific requirements 

for structured abstracts are as follows: 

An informative, structured abstracts of no more than 480 

words should accompany each manuscript. Abstracts for original 

contributions should be structured into the following sections. AIM 

(no more than 20 words): Only the purpose should be included. 

Please write the aim as the form of “To investigate/study/…; 

MATERIALS AND METHODS (no more than 140 words); 

RESULTS (no more than 294 words): You should present P values 

where appropriate and must provide relevant data to illustrate 

how they were obtained, e.g. 6.92 ± 3.86 vs 3.61 ± 1.67, P < 0.001; 

CONCLUSION (no more than 26 words). 

Key words 

Please list 5-10 key words, selected mainly from Index Medicus, which 

reflect the content of the study. 

Text 

For articles of these sections, original articles and brief articles, the 

main text should be structured into the following sections: INTRO- 



DUCTION, MATERIALS AND METHODS, RESULTS and 

DISCUSSION, and should include appropriate Figures and Tables. 

Data should be presented in the main text or in Figures and Tables, 

but not in both. The main text format of these sections, editorial, 

topic highlight, case report, letters to the editors, can be found at: 

http://www.wjgnet.com/1949-8470/g_info_20100313183720.htm. 

Illustrations 

Figures should be numbered as 1, 2, 3, etc., and mentioned clearly 

in the main text. Provide a brief title for each figure on a separate 

page. Detailed legends should not be provided under the 

figures. This part should be added into the text where the figures 

are applicable. Figures should be either Photoshop or Illustrator 

files (in tiff, eps, jpeg formats) at high-resolution. Examples 

can be found at: http://www.wjgnet.com/1007-9327/13/4520. 

pdf; http://www.wjgnet.com/1007-9327/13/4554.pdf; http:// 

www.wjgnet.com/1007-9327/13/4891.pdf; http://www. 

wjgnet.com/1007-9327/13/4986.pdf; http://www.wjgnet. 

com/1007-9327/13/4498.pdf. Keeping all elements compiled is 

necessary in line-art image. Scale bars should be used rather than 

magnification factors, with the length of the bar defined in the legend 

rather than on the bar itself. File names should identify the figure 

and panel. Avoid layering type directly over shaded or textured 

areas. Please use uniform legends for the same subjects. For example: 

Figure 1 Pathological changes in atrophic gastritis after treatment. 

A: ...; B: ...; C: ...; D: ...; E: ...; F: ...; G: …etc. It is our principle 

to publish high resolution-figures for the printed and E-versions. 

Tables 

Three-line tables should be numbered 1, 2, 3, etc., and mentioned 

clearly in the main text. Provide a brief title for each table. Detailed 

legends should not be included under tables, but rather added into 

the text where applicable. The information should complement, 

but not duplicate the text. Use one horizontal line under the title, a 

second under column heads, and a third below the Table, above any 

footnotes. Vertical and italic lines should be omitted. 

Notes in tables and illustrations 

Data that are not statistically significant should not be noted. a P < 

0.05, b P < 0.01 should be noted (P > 0.05 should not be noted). If 

there are other series of P values, c P < 0.05 and d P < 0.01 are used. 

A third series of P values can be expressed as e P < 0.05 and f P < 0.01. 

Other notes in tables or under illustrations should be expressed as 

1 F, 2 F, 3 F; or sometimes as other symbols with a superscript (Arabic 

numerals) in the upper left corner. In a multi-curve illustration, each 

curve should be labeled with ●, ○, ■, □, ▲, △, etc., in a certain sequence. 

Acknowledgments 

Brief acknowledgments of persons who have made genuine contributions 

to the manuscript and who endorse the data and conclusions 

should be included. Authors are responsible for obtaining 

written permission to use any copyrighted text and/or illustrations. 

REFERENCES 

Coding system 

The author should number the references in Arabic numerals according 

to the citation order in the text. Put reference numbers in 

square brackets in superscript at the end of citation content or after 

the cited author’s name. For citation content which is part of the 

narration, the coding number and square brackets should be typeset 

normally. For example, “Crohn’s disease (CD) is associated with 

increased intestinal permeability [1,2] ”. If references are cited directly 

in the text, they should be put together within the text, for example, 

“From references [19,22-24] , we know that...” 

When the authors write the references, please ensure that the 

order in text is the same as in the references section, and also ensure 

the spelling accuracy of the first author’s name. Do not list the same 

citation twice. 

III March 28, 2011|Volume 3|Issue 3|


PMID and DOI 

Pleased provide PubMed citation numbers to the reference list, e.g. 

PMID and DOI, which can be found at http://www.ncbi.nlm.nih. 

gov/sites/entrez?db=pubmed and http://www.crossref.org/SimpleTextQuery/, 

respectively. The numbers will be used in E-version 

of this journal. 

Style for journal references 

Authors: the name of the first author should be typed in bold-faced 

letters. The family name of all authors should be typed with the initial 

letter capitalized, followed by their abbreviated first and middle 

initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo- 

Rong Pan as Pan BR). The title of the cited article and italicized 

journal title (journal title should be in its abbreviated form as shown 

in PubMed), publication date, volume number (in black), start page, 

and end page [PMID: 11819634 DOI: 10.3748/wjg.13.5396]. 

Style for book references 

Authors: the name of the first author should be typed in bold-faced 

letters. The surname of all authors should be typed with the initial 

letter capitalized, followed by their abbreviated middle and first 

initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo- 

Rong Pan as Pan BR) Book title. Publication number. Publication 

place: Publication press, Year: start page and end page. 

Format 

Journals 

English journal article (list all authors and include the PMID where applicable) 

1 Jung EM, Clevert DA, Schreyer AG, Schmitt S, Rennert J, 

Kubale R, Feuerbach S, Jung F. Evaluation of quantitative contrast 

harmonic imaging to assess malignancy of liver tumors: 

A prospective controlled two-center study. World J Gastroenterol 

2007; 13: 6356-6364 [PMID: 18081224 DOI: 10.3748/wjg.13. 

6356] 

Chinese journal article (list all authors and include the PMID where applicable) 

2 Lin GZ, Wang XZ, Wang P, Lin J, Yang FD. Immunologic 

effect of Jianpi Yishen decoction in treatment of Pixu-diarrhoea. 

Shijie Huaren Xiaohua Zazhi 1999; 7: 285-287 

In press 

3 Tian D, Araki H, Stahl E, Bergelson J, Kreitman M. Signature 

of balancing selection in Arabidopsis. Proc Natl Acad Sci USA 

2006; In press 

Organization as author 

4 Diabetes Prevention Program Research Group. Hypertension, 

insulin, and proinsulin in participants with impaired glucose 

tolerance. Hypertension 2002; 40: 679-686 [PMID: 12411462 

PMCID:2516377 DOI:10.1161/01.HYP.0000035706.28494. 

09] 

Both personal authors and an organization as author 

5 Vallancien G, Emberton M, Harving N, van Moorselaar RJ; 

Alf-One Study Group. Sexual dysfunction in 1, 274 European 

men suffering from lower urinary tract symptoms. J Urol 

2003; 169: 2257-2261 [PMID: 12771764 DOI:10.1097/01.ju. 

0000067940.76090.73] 

No author given 

6 21st century heart solution may have a sting in the tail. BMJ 

2002; 325: 184 [PMID: 12142303 DOI:10.1136/bmj.325. 

7357.184] 

Volume with supplement 

7 Geraud G, Spierings EL, Keywood C. Tolerability and safety 

of frovatriptan with short- and long-term use for treatment 

of migraine and in comparison with sumatriptan. Headache 

2002; 42 Suppl 2: S93-99 [PMID: 12028325 DOI:10.1046/ 

j.1526-4610.42.s2.7.x] 

Issue with no volume 

8 Banit DM, Kaufer H, Hartford JM. Intraoperative frozen 

section analysis in revision total joint arthroplasty. Clin Orthop 

Relat Res 2002; (401): 230-238 [PMID: 12151900 DOI:10.10 

97/00003086-200208000-00026] 


No volume or issue 

9 Outreach: Bringing HIV-positive individuals into care. HRSA 

Careaction 2002; 1-6 [PMID: 12154804] 

Books 

Personal author(s) 

10 Sherlock S, Dooley J. Diseases of the liver and billiary system. 

9th ed. Oxford: Blackwell Sci Pub, 1993: 258-296 

Chapter in a book (list all authors) 

11 Lam SK. Academic investigator’s perspectives of medical 

treatment for peptic ulcer. In: Swabb EA, Azabo S. Ulcer 

disease: investigation and basis for therapy. New York: Marcel 

Dekker, 1991: 431-450 

Author(s) and editor(s) 

12 Breedlove GK, Schorfheide AM. Adolescent pregnancy. 

2nd ed. Wieczorek RR, editor. White Plains (NY): March of 

Dimes Education Services, 2001: 20-34 

Conference proceedings 

13 Harnden P, Joffe JK, Jones WG, editors. Germ cell tumours V. 

Proceedings of the 5th Germ cell tumours Conference; 2001 

Sep 13-15; Leeds, UK. New York: Springer, 2002: 30-56 

Conference paper 

14 Christensen S, Oppacher F. An analysis of Koza's computational 

effort statistic for genetic programming. In: Foster JA, 

Lutton E, Miller J, Ryan C, Tettamanzi AG, editors. Genetic 

programming. EuroGP 2002: Proceedings of the 5th European 

Conference on Genetic Programming; 2002 Apr 3-5; 

Kinsdale, Ireland. Berlin: Springer, 2002: 182-191 

Electronic journal (list all authors) 

15 Morse SS. Factors in the emergence of infectious diseases. 

Emerg Infect Dis serial online, 1995-01-03, cited 1996-06-05; 

1(1): 24 screens. Available from: URL: http://www.cdc.gov/ 

ncidod/eid/index.htm 

Patent (list all authors) 

16 Pagedas AC, inventor; Ancel Surgical R&D Inc., assignee. 

Flexible endoscopic grasping and cutting device and positioning 

tool assembly. United States patent US 20020103498. 2002 Aug 

1 

Statistical data 

Write as mean ± SD or mean ± SE. 

Statistical expression 

Express t test as t (in italics), F test as F (in italics), chi square test as 

χ 2 (in Greek), related coefficient as r (in italics), degree of freedom 

as υ (in Greek), sample number as n (in italics), and probability as P (in 

italics). 

Units 

Use SI units. For example: body mass, m (B) = 78 kg; blood pressure, 

p (B) = 16.2/12.3 kPa; incubation time, t (incubation) = 96 h, 

blood glucose concentration, c (glucose) 6.4 ± 2.1 mmol/L; blood 

CEA mass concentration, p (CEA) = 8.6 24.5 mg/L; CO 2 volume 

fraction, 50 mL/L CO 2, not 5% CO 2; likewise for 40 g/L formaldehyde, 

not 10% formalin; and mass fraction, 8 ng/g, etc. Arabic 

numerals such as 23, 243, 641 should be read 23 243 641. 

The format for how to accurately write common units and 

quantums can be found at: http://www.wjgnet.com/1949-8470/ 

g_info_20100313185816.htm. 

Abbreviations 

Standard abbreviations should be defined in the abstract and on 

first mention in the text. In general, terms should not be abbreviated 

unless they are used repeatedly and the abbreviation is helpful 

to the reader. Permissible abbreviations are listed in Units, Symbols 

and Abbreviations: A Guide for Biological and Medical Editors and 

Authors (Ed. Baron DN, 1988) published by The Royal Society of 

Medicine, London. Certain commonly used abbreviations, such as 

DNA, RNA, HIV, LD50, PCR, HBV, ECG, WBC, RBC, CT, ESR, 

CSF, IgG, ELISA, PBS, ATP, EDTA, mAb, can be used directly 

without further explanation. 

IV March 28, 2011|Volume 3|Issue 3|

Italics 

Quantities: t time or temperature, c concentration, A area, l length, 

m mass, V volume. 

Genotypes: gyrA, arg 1, c myc, c fos, etc. 

Restriction enzymes: EcoRI, HindI, BamHI, Kbo I, Kpn I, etc. 

Biology: H. pylori, E coli, etc. 

Examples for paper writing 

Editorial: http://www.wjgnet.com/1949-8470/g_info_20100313 

182341.htm 

Frontier: http://www.wjgnet.com/1949-8470/g_info_2010031318 

2448.htm 

Topic highlight: http://www.wjgnet.com/1949-8470/g_info_201003 

13182639.htm 

Observation: http://www.wjgnet.com/1949-8470/g_info_20100313 

182834.htm 

Guidelines for basic research: http://www.wjgnet.com/1949-8470/ 

g_info_20100313183057.htm 

Guidelines for clinical practice: http://www.wjgnet.com/1949- 

8470/g_info_20100313183238.htm 

Review: http://www.wjgnet.com/1949-8470/g_info_20100313 

183433.htm 

Original articles: http://www.wjgnet.com/1949-8470/g_info_2010 

0313183720.htm 

Brief articles: http://www.wjgnet.com/1949-8470/g_info_201003 

13184005.htm 

Case report: http://www.wjgnet.com/1949-8470/g_info_20100313 

184149.htm 

Letters to the editor: http://www.wjgnet.com/1949-8470/g_info_20 

100313184410.htm 

Book reviews: http://www.wjgnet.com/1949-8470/g_info_201003 

13184803.htm 

Guidelines: http://www.wjgnet.com/1949-8470/g_info_20100313 

185047.htm 

SUBMISSION OF THE REVISED MANUSCRIPTS 

AFTER ACCEPTED 

Please revise your article according to the revision policies of WJR. 

The revised version including manuscript and high-resolution image 

figures (if any) should be re-submitted or uploaded online. The 

author should send copyright transfer letter, and responses to the 

reviewers and science news to us via email. 

Editorial Office 


Editorial Department: Room 903, Building D, 



Ocean International Center, No. 62 Dongsihuan Zhonglu, 

Chaoyang District, Beijing 100025, China 



Telephone: +86-10-85381892 

Fax: +86-10-85381893 

Language evaluation 

The language of a manuscript will be graded before it is sent for 

revision. (1) Grade A: priority publishing; (2) Grade B: minor language 

polishing; (3) Grade C: a great deal of language polishing 

needed; and (4) Grade D: rejected. Revised articles should reach 

Grade A or B. 

Copyright assignment form 

Please download a Copyright assignment form from http://www. 

wjgnet.com/1949-8470/g_info_20100313185522.htm. 

Responses to reviewers 

Please revise your article according to the comments/suggestions 

provided by the reviewers. The format for responses to the reviewers’ 

comments can be found at: http://www.wjgnet.com/1949-8470/ 

g_info_20100313185358.htm. 

Proof of financial support 

For paper supported by a foundation, authors should provide a 

copy of the document and serial number of the foundation. 

Links to documents related to the manuscript 

WJR will be initiating a platform to promote dynamic interactions between 

the editors, peer reviewers, readers and authors. After a manuscript 

is published online, links to the PDF version of the submitted 

manuscript, the peer-reviewers’ report and the revised manuscript will 

be put on-line. Readers can make comments on the peer reviewer’s 

report, authors’ responses to peer reviewers, and the revised manuscript. 

We hope that authors will benefit from this feedback and be 

able to revise the manuscript accordingly in a timely manner. 

Science news releases 

Authors of accepted manuscripts are suggested to write a science 

news item to promote their articles. The news will be released rapidly 

at EurekAlert/AAAS (http://www.eurekalert.org). The title for 

news items should be less than 90 characters; the summary should 

be less than 75 words; and main body less than 500 words. Science 

news items should be lawful, ethical, and strictly based on your 

original content with an attractive title and interesting pictures. 

Publication fee 

WJR is an international, peer-reviewed, Open-Access, online journal. 

Articles published by this journal are distributed under the 

terms of the Creative Commons Attribution Non-commercial 

License, which permits use, distribution, and reproduction in any 

medium, provided the original work is properly cited, the use is 

non commercial and is otherwise in compliance with the license. 

Authors of accepted articles must pay a publication fee. The related 

standards are as follows. Publication fee: 1300 USD per article; 

Reprints fee: 350 USD per 100 reprints, including postage cost. 

Editorial, topic highlights, book reviews and letters to the editor 

are published free of charge. 

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